Submissions for variant NM_000059.4(BRCA2):c.5164A>T (p.Ser1722Cys)

gnomAD frequency: 0.00003  dbSNP: rs80358741

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218602	SCV000275165	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-22	criteria provided, single submitter	clinical testing	The p.S1722C variant (also known as c.5164A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 5164. The serine at codon 1722 is replaced by cysteine, an amino acid with dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with an osteosarcoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637658	SCV000759127	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1722 of the BRCA2 protein (p.Ser1722Cys). This variant is present in population databases (rs80358741, gnomAD 0.007%). This missense change has been observed in individual(s) with osteosarcoma (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 37948). 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.
Counsyl	RCV000031529	SCV000785107	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001787821	SCV002030094	uncertain significance	Pancreatic cancer, susceptibility to, 2	2021-05-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800326	SCV002046716	uncertain significance	not provided	2021-03-15	criteria provided, single submitter	clinical testing
Mendelics	RCV002247403	SCV002517980	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000218602	SCV003847043	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).
All of Us Research Program, National Institutes of Health	RCV004803040	SCV005424468	uncertain significance	BRCA2-related cancer predisposition	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 1722 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 been identified in 1/233676 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.
Sharing Clinical Reports Project (SCRP)	RCV000031529	SCV000054134	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-09-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031529	SCV000146552	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing