Submissions for variant NM_000059.4(BRCA2):c.6513_6514delinsCG (p.Ser2172Ala)

dbSNP: rs1064794089

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484681	SCV000567790	uncertain significance	not provided	2019-04-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538024	SCV000635513	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2172 of the BRCA2 protein (p.Ser2172Ala). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 419761). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781046	SCV000918825	uncertain significance	not specified	2018-02-19	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6513_6514delinsCG (p.Ser2172Ala) variant involves the alteration of a dinucleotide non-conserved sequence (GT>CG). Five out of five in silico analyses predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was not observed in 263870 control chromosomes (gnomAD). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) classify the variant as "uncertain significance." Note, the single nucleotide change, c.6514T>G, causes the same missense change and has been reported by a clinical diagnostic laboratory (ClinVar submission) and a reputable database as "uncertain significance." Based on the available evidence, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV001180875	SCV001345922	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-12	criteria provided, single submitter	clinical testing	This missense variant replaces serine with alanine at codon 2172 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001180875	SCV003847542	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).
Ambry Genetics	RCV001180875	SCV003855528	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	The c.6513_6514delGTinsCG variant (also known as p.S2172A), located in coding exon 10 of the BRCA2 gene, results from an in-frame deletion of GT and insertion of CG at nucleotide positions 6513 to 6514. This results in the substitution of the serine residue for an alanine residue at codon 2172, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.