Submissions for variant NM_000059.4(BRCA2):c.3152T>C (p.Leu1051Ser)

dbSNP: rs778281493

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470166	SCV000549586	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1051 of the BRCA2 protein (p.Leu1051Ser). This variant is present in population databases (rs778281493, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21120943, 21520333, 35264596, 35534704). ClinVar contains an entry for this variant (Variation ID: 409474). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000571433	SCV000661190	likely benign	Hereditary cancer-predisposing syndrome	2023-01-21	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.
Color Diagnostics, LLC DBA Color Health	RCV000571433	SCV000903830	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 1051 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001410) and in individuals suspected to be at-risk for hereditary breast and ovarian cancer (PMID: 21120943, 35534704). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on tumor pathology of 0.3922 (PMID: 31131967). This variant has been identified in 1/246462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics	RCV000989021	SCV001139057	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000571433	SCV003851721	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).