Submissions for variant NM_007294.4(BRCA1):c.2416G>A (p.Ala806Thr)

gnomAD frequency: 0.00001  dbSNP: rs80357144

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047832	SCV000075845	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000212167	SCV000209939	likely benign	not specified	2017-10-02	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	RCV000218307	SCV000274017	likely benign	Hereditary cancer-predisposing syndrome	2019-04-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212167	SCV000698950	uncertain significance	not specified	2019-05-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2416G>A (p.Ala806Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250528 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2416G>A has been reported in the literature in individuals affected with breast cancer (e.g. Borg_2010) without strong evidence of causality. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. In addition, a functional study reports that this variant has no impact on homologous recombination activity of BRCA1 protein (Lu_2015). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation ((1x uncertain significance and 2x likely benign). Based on the evidence outlined above, the variant was classified as VUS - possibly benign until additional clinical and functional evidence becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000218307	SCV000909344	likely benign	Hereditary cancer-predisposing syndrome	2018-05-31	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000077517	SCV002584651	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2022-09-22	criteria provided, single submitter	clinical testing	The BRCA1 c.2416G>A (p.Ala806Thr) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. A homology-directed repair assay indicated that this variant is similar to the wild-type (PMID: 26689913). This variant has been identified in individuals with a personal and/or family history of breast cancer (PMID: 20104584, 20127978). It is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000218307	SCV003847682	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).
Sharing Clinical Reports Project (SCRP)	RCV000077517	SCV000109318	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2009-04-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077517	SCV000144423	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2001-10-29	no assertion criteria provided	clinical testing