Submissions for variant NM_007294.4(BRCA1):c.3707A>G (p.Asn1236Ser)

gnomAD frequency: 0.00001  dbSNP: rs863224760

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000198979	SCV000254980	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1236 of the BRCA1 protein (p.Asn1236Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 25802882, 29215753, 30287823, 32546644). ClinVar contains an entry for this variant (Variation ID: 216665). 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. 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.
GeneDx	RCV000424940	SCV000512302	likely benign	not specified	2016-06-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000510050	SCV000607968	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	The p.N1236S variant (also known as c.3707A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3707. The asparagine at codon 1236 is replaced by serine, an amino acid with highly similar properties. This alteration was detected in 1/135 Japanese individuals diagnosed with breast and/or ovarian cancer (Hirotsu Y et al. Mol Genet Genomic Med, 2015 Mar;3:121-9). This alteration was observed with an allele frequency of 0.00014 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00044 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0004 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration has been reported with a carrier frequency of 0.00039 in 7636 unselected prostate cancer patients and 0.0004 in 12366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). This variant has been identified in 4/12503 unselected Japanese colorectal cancer patients and in 10/23705 controls (Fujita M et al. Clin Gastroenterol Hepatol, 2022 09;20:2132-2141.e9).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	RCV000510050	SCV003850051	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358174	SCV001553845	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.N1236S variant was identified in 3 individuals with breast and/or ovarian cancer (Nakagomi_2018_PMID: 29215753; Hirotsu_2015_PMID: 25802882). The variant was identified in dbSNP (ID: rs863224760) and ClinVar (classified as likely benign by GeneDx and as uncertain significance by Ambry Genetics and Invitae). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (March 6, 2019, v2.1.1). The p.N1236 residue is conserved in mammals however computational analyses (MUT Assesor, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.