Submissions for variant NM_007294.4(BRCA1):c.2228A>G (p.Asn743Ser)

dbSNP: rs1567796489

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000773409	SCV000907103	uncertain significance	Hereditary cancer-predisposing syndrome	2019-01-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071988	SCV001237329	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-14	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 628747). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 743 of the BRCA1 protein (p.Asn743Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824878	SCV002074190	uncertain significance	not specified	2022-01-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2228A>G (p.Asn743Ser) results in a conservative amino acid change in the encoded protein sequence. This variant is also known as 2347A>G in HGVS. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251100 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2228A>G is reported in atleast one individual affected with Hereditary Breast and/or Ovarian Cancer without evidence for causality (Dorling_2021). To our knowledge no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV000773409	SCV002730881	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-20	criteria provided, single submitter	clinical testing	The p.N743S variant (also known as c.2228A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 2228. The asparagine at codon 743 is replaced by serine, an amino acid with highly similar properties. This amino acid position is poorly 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	RCV000773409	SCV003847836	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).