Submissions for variant NM_000059.4(BRCA2):c.4436G>A (p.Ser1479Asn)

dbSNP: rs80358678

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001305185	SCV001494508	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-03-23	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BRCA2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 1479 of the BRCA2 protein (p.Ser1479Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine.
Color Diagnostics, LLC DBA Color Health	RCV001523986	SCV001733732	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-04	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 1479 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 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.
Ambry Genetics	RCV001523986	SCV002631294	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-16	criteria provided, single submitter	clinical testing	The p.S1479N variant (also known as c.4436G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 4436. The serine at codon 1479 is replaced by asparagine, an amino acid with highly similar properties. This alteration was detected in a cohort of 230 high-risk breast cancer patients from China (Su Y et al. Front Genet, 2021 Nov;12:674094). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001523986	SCV003850508	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).