ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3707A>G (p.Asn1236Ser) (rs863224760)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198979 SCV000254980 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-10-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1236 of the BRCA1 protein (p.Asn1236Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 29215753, 30287823, 25802882). ClinVar contains an entry for this variant (Variation ID: 216665). 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 serine 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. 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 2017-03-27 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 breast and/or ovarian cancer patients, and it was called a variant of uncertain significance (Hirotsu Y et al. Mol Genet Genomic Med, 2015 Mar;3:121-9). 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.
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.

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