Submissions for variant NM_000059.4(BRCA2):c.7916C>T (p.Pro2639Leu)

gnomAD frequency: 0.00001  dbSNP: rs774723315

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199791	SCV000254216	likely benign	Hereditary breast ovarian cancer syndrome	2024-07-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000213138	SCV000274929	likely benign	Hereditary cancer-predisposing syndrome	2020-02-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
PreventionGenetics, part of Exact Sciences	RCV000679188	SCV000805770	uncertain significance	not provided	2017-12-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679188	SCV000889138	uncertain significance	not provided	2021-06-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213138	SCV000911810	likely benign	Hereditary cancer-predisposing syndrome	2018-02-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000499513	SCV000916954	uncertain significance	not specified	2018-06-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7916C>T (p.Pro2639Leu) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246060 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.7916C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Deihimi_2017, Jakimovska_2018, Schenkel_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.5645C>A, p.Ser1882X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneDx	RCV000679188	SCV003918460	uncertain significance	not provided	2023-04-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: no impact on homology-directed repair (HDR) activity (Hart et al., 2019; Richardson et al., 2021; Iversen et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with personal and family history of breast cancer (Jakimovska et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8144C>T; This variant is associated with the following publications: (PMID: 32444794, 33609447, 29884841, 29335924, 35665744, 12228710)
Sharing Clinical Reports Project (SCRP)	RCV000239039	SCV000297556	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2013-12-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353687	SCV000592158	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Pro2639Leu variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, ClinVar, or BIC databases. The variant was identified in UMD in one sample (as an unclassified variant); this sample had a co-occurring pathogenic BRCA2 variant (c.5645C>A (p.Ser1882X)), increasing the likelihood that the p.Pro2639Leu variant does not have clinical significance. The p.Pro2639 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Pro2639Leu variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.