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Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

Li, H. ; Borg, Åke LU and Goldgar, David E. (2022) In Genetics in Medicine 24(1). p.119-129
Abstract
Purpose

Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.
Methods

We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis.
Results

Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than... (More)
Purpose

Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.
Methods

We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis.
Results

Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs.
Conclusion

These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes. (Less)
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author
; and
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Genetics in Medicine
volume
24
issue
1
pages
119 - 129
publisher
Nature Publishing Group
external identifiers
  • scopus:85122352590
  • pmid:34906479
ISSN
1098-3600
DOI
10.1016/j.gim.2021.08.016
language
English
LU publication?
yes
id
db36201a-d6e9-4465-808a-e19d8829deb5
date added to LUP
2023-01-12 12:59:04
date last changed
2023-01-13 03:00:08
@article{db36201a-d6e9-4465-808a-e19d8829deb5,
  abstract     = {{Purpose<br/><br/>Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for &gt;2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.<br/>Methods<br/><br/>We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis.<br/>Results<br/><br/>Estimated breast cancer risks were markedly lower for women aged &gt;50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged &gt;50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs.<br/>Conclusion<br/><br/>These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.}},
  author       = {{Li, H. and Borg, Åke and Goldgar, David E.}},
  issn         = {{1098-3600}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{119--129}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Genetics in Medicine}},
  title        = {{Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants}},
  url          = {{http://dx.doi.org/10.1016/j.gim.2021.08.016}},
  doi          = {{10.1016/j.gim.2021.08.016}},
  volume       = {{24}},
  year         = {{2022}},
}