Submissions for variant NM_007294.4(BRCA1):c.2620A>C (p.Asn874His)

dbSNP: rs1064795862

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479303	SCV000572065	uncertain significance	not provided	2021-03-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2739A>C; Observed in individuals with a family history of breast or ovarian cancer (Anczukow 2008); This variant is associated with the following publications: (PMID: 18273839, 23893897, 25348012)
Invitae	RCV000545763	SCV000635859	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 874 of the BRCA1 protein (p.Asn874His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18273839). ClinVar contains an entry for this variant (Variation ID: 422565). 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.
Ambry Genetics	RCV000570820	SCV000668454	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-12	criteria provided, single submitter	clinical testing	The p.N874H variant (also known as c.2620A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 2620. The asparagine at codon 874 is replaced by histidine, an amino acid with similar properties. This amino acid position is not well 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.
Color Diagnostics, LLC DBA Color Health	RCV000570820	SCV000910431	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 874 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a suspected hereditary breast and ovarian cancer family (PMID: 18273839). This variant has been identified in 1/251142 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479303	SCV001470163	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251142 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been predicted to have no impact on splicing (PMIDs: 26913838 (2016), 31853058 (2020), 32741062 (2020), and 33087888 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000479303	SCV001472383	uncertain significance	not provided	2019-10-22	criteria provided, single submitter	clinical testing	The BRCA1 c.2620A>C; p.Asn874His variant (rs1064795862) is reported in the literature in a family with affected with breast and/or ovarian cancer, but its clinical significance was not determined (Anczukow 2008). This variant is found on a single chromosome in the Genome Aggregation Database (1/251142 alleles), indicating it is not a common polymorphism. The asparagine at codon 874 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Asn874His variant is uncertain at this time. References: Anczukow O et al. Unclassified variants identified in BRCA1 exon 11: Consequences on splicing. Genes Chromosomes Cancer. 2008 May;47(5):418-26.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000570820	SCV003851029	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401547	SCV004122630	uncertain significance	not specified	2023-10-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2620A>C (p.Asn874His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251142 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2620A>C has been reported in the literature in nonspecified individual(s) affected with Breast and Ovarian Cancer, without strong evidence for causality (example, Anczukow_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 18273839). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=6, Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.