Submissions for variant NM_007294.4(BRCA1):c.5512G>A (p.Val1838Met)

dbSNP: rs730881501

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160014	SCV000210230	uncertain significance	not provided	2014-02-25	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5512G>A at the cDNA level, p.Val1838Met (V1838M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Val1838Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution and is unlikely to affect protein integrity. BRCA1 Val1838Met occurs at a position that is well conserved across species and is located in the BRCT2 domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Val1838Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689723	SCV000817388	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1838 of the BRCA1 protein (p.Val1838Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 182173). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). This variant disrupts the p.Val1838 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18375895, 20516115, 21990134, 27272900). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Diagnostics, LLC DBA Color Health	RCV001181283	SCV001346394	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1838 of the BRCA1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. This variant has been reported to be functional in a haploid cell proliferation assay (PMID: 30209399). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. Different variants affecting the same position (p.Val1838Glu and p.Val1838Gly) are considered to be disease-causing (ClinVar variation ID: 55611, 254643), suggesting that valine at this position is important for protein structure and function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.
Ambry Genetics	RCV001181283	SCV002648678	likely benign	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Brotman Baty Institute, University of Washington	RCV001078020	SCV001244043	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro