Submissions for variant NM_000059.4(BRCA2):c.3453C>G (p.Ile1151Met)

gnomAD frequency: 0.00001  dbSNP: rs80358592

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001086601	SCV000072212	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132398	SCV000187490	likely benign	Hereditary cancer-predisposing syndrome	2018-09-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001703436	SCV000210591	likely benign	not provided	2021-03-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10923033, 21952622, 25348012, 27062684, 27878467)
Counsyl	RCV000031423	SCV000487790	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132398	SCV000688807	likely benign	Hereditary cancer-predisposing syndrome	2017-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212229	SCV000694694	uncertain significance	not specified	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3453C>G (p.Ile1151Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250978 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.3453C>G has been reported in the literature in at least one individual affected with prostate cancer (Kote-Jarai_2011), one individual affected with breast cancer and/or ovarian cancer (Azzollini_2016), and one individual who was previously tested negative for BRCA 1/2 mutation and retested using multigene panels (Yadav_2017), and in one female without cancer, but potentially before age-of-onset (Dong_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with another pathogenic variant have been reported (BRCA2 c.4470dupA, p.Leu1491Thr fs*23), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories classified the variant as VUS (n=3) or likely benign (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance - possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001703436	SCV002046781	uncertain significance	not provided	2020-10-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132398	SCV002533797	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132398	SCV003851976	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP)	RCV000031423	SCV000054028	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2013-06-04	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031423	SCV000146237	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing