Submissions for variant NM_007294.4(BRCA1):c.1243G>A (p.Val415Ile)

gnomAD frequency: 0.00006  dbSNP: rs587782770

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132298	SCV000187383	likely benign	Hereditary cancer-predisposing syndrome	2020-11-03	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081676	SCV000218586	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588638	SCV000296369	likely benign	not provided	2022-09-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000238907	SCV000489338	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000588638	SCV000565925	uncertain significance	not provided	2017-12-07	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1243G>A at the cDNA level, p.Val415Ile (V415I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). Using alternate nomenclature, this variant would be defined as BRCA1 1362G>A. This variant has been observed in at least one individual with triple negative breast cancer (Muendlein 2015). BRCA1 Val415Ile was observed at an allele frequency of 0.03% (9/25,778) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Val415Ile is located in a region known to interact with multiple proteins (Paul 2014). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Val415Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797635	SCV000698839	likely benign	not specified	2021-11-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1243G>A (p.Val415Ile) results in a conservative amino acid change located in the BRCA1, serine-rich domain (IPR025994) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 298260 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.0001 vs 0.001), allowing no conclusion about variant significance. c.1243G>A has been reported in the literature as a VUS in settings of multigene panel testing of individuals affected with breast and/or ovarian cancer (example, Muendien_2015, Chan_2018, Momozawa_2018, Wang_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A study reporting the outcomes of large scale multifactorial likelihood quantitative analysis of BRCA1 variants classifies this variant as IARC class 2 (Likely benign) (Parsons_2019) and has been recently cited by another study (Lyra_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001081676	SCV000890996	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-08-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132298	SCV000910915	likely benign	Hereditary cancer-predisposing syndrome	2017-08-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132298	SCV002538008	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-01	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000588638	SCV002585649	likely benign	not provided	2022-08-01	criteria provided, single submitter	clinical testing	BRCA1: BP1
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132298	SCV003846078	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).
Department of Medical and Surgical Sciences, University of Bologna	RCV000238907	SCV004228327	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	BS1(Strong)+BP1(Strong)+BP5(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
BRCAlab, Lund University	RCV000238907	SCV004244132	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing