Submissions for variant NM_000059.4(BRCA2):c.7661G>A (p.Ser2554Asn)

dbSNP: rs398122588

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160136	SCV000210439	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7889G>A; This variant is associated with the following publications: (PMID: 12228710)
Ambry Genetics	RCV000215704	SCV000274314	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-25	criteria provided, single submitter	clinical testing	The p.S2554N variant (also known as c.7661G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7661. The serine at codon 2554 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637761	SCV000759238	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2554 of the BRCA2 protein (p.Ser2554Asn). This variant is present in population databases (rs398122588, gnomAD 0.003%). 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: 91489). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000160136	SCV001148992	uncertain significance	not provided	2018-12-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160136	SCV002046531	uncertain significance	not provided	2020-12-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000215704	SCV002531878	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000077006	SCV004844452	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 2554 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 1/251154 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.
Fulgent Genetics, Fulgent Genetics	RCV005007988	SCV005633972	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-04-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077006	SCV000108803	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2007-08-27	no assertion criteria provided	clinical testing