Submissions for variant NM_007294.4(BRCA1):c.5216A>T (p.Asp1739Val)

dbSNP: rs80357227

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000520251	SCV000605908	likely pathogenic	not provided	2020-03-11	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Conflicting predictions of the effect on the protein. Located in potentially critical domain of the protein. Found in at least one patient with expected phenotype for this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
GeneDx	RCV000520251	SCV000617446	likely pathogenic	not provided	2017-04-21	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5216A>T at the cDNA level, p.Asp1739Val (D1739V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). Using alternate nomenclature, this variant would be defined as BRCA1 5335A>T. This variant has been observed in at least two ovarian cancer patients with a family history of breast and/or ovarian cancer (Laplace-Marieze 1999, Ricevuto 2001). In functional studies this variant displayed impaired structural stability, binding activity, binding specificity, protein folding, transcription activity, cisplatin response, and ability to support growth (Lee 2010, Bouwman 2013). BRCA1 Asp1739Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Asp1739Val occurs at a position that is conserved in mammals and is located in the region of interaction with BRCA2 and multiple other proteins (Chen 1998, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider BRCA1 Asp1739Val to be a likely pathogenic variant.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000614231	SCV000743376	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378028	SCV001575509	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1739 of the BRCA1 protein (p.Asp1739Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with stomach and ovarian cancer (PMID: 10200350). ClinVar contains an entry for this variant (Variation ID: 55466). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 23867111, 28781887, 30209399, 30765603). This variant disrupts the p.Asp1739 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12827452, 15800311, 19491284, 20516115, 23867111). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000614231	SCV000733594	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000614231	SCV001241943	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000520251	SCV001956225	pathogenic	not provided		no assertion criteria provided	clinical testing