Submissions for variant NM_000059.4(BRCA2):c.4915G>A (p.Val1639Ile)

gnomAD frequency: 0.00006  dbSNP: rs80358716

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083151	SCV000072532	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129029	SCV000172937	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240704	SCV000265941	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Counsyl	RCV000031513	SCV000488073	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000587911	SCV000512365	likely benign	not provided	2020-01-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22811390, 10923033, 24916970, 22476429, 27257965, 24817641, 30287823, 30702160, 31131967, 30410429, 31825140)
Color Diagnostics, LLC DBA Color Health	RCV000129029	SCV000537492	likely benign	Hereditary cancer-predisposing syndrome	2015-07-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004562220	SCV000694811	likely benign	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4915G>A (p.Val1639Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 247782 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4915G>A has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with Breast/Ovarian/Uterine Cancer (e.g. Lu_2012, Peixoto_2014, Pennington_2013, Zhong_2016, Tanabe_2016, Bhaskaran_2019, Momozawa_2018), or in unaffected controls (e.g. Momozawa_2018, Okawa_2023), however these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variants have been reported in the BIC database and observed at our laboratory (BIC - BRCA1 c.2457_2457delC; BRCA1 whole gene deletion; Our laboratory - BRCA2 c.5073dupA, p.Trp1692fsX3; BRCA1 c.5324T>G, p.Met1775Arg), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as likely benign (n=5) or uncertain significance (n=3). Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587911	SCV002047325	likely benign	not provided	2023-05-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129029	SCV002533910	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-25	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129029	SCV003852202	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)	RCV000031513	SCV000054118	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-11-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031513	SCV000146505	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing