Submissions for variant NM_007294.4(BRCA1):c.3082C>T (p.Arg1028Cys)

gnomAD frequency: 0.00001  dbSNP: rs80357049

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566762	SCV004101422	benign	BRCA1-related cancer predisposition	2024-06-11	reviewed by expert panel	curation	The c.3082C>T variant in BRCA1 is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 1028 (p.Arg1028Cys). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0.01, score threshold < 0.1) (BP1_Strong met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 32546644) (BS3 met). This variant has been observed in one individual with features considered inconsistent with an FA-associated phenotype, variant is homozygous (total score 1 point) (BS2_Supporting met; PMID: 29435075). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0009 (based on Cosegregation LR=0.131; Pathology LR=0.056; Co-occurrence LR= 1.527; Family History LR= 0.081), below the thresholds for very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 31131967). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong, BS3, BS2_Supporting, BP5_Very strong).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048066	SCV000076079	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000165900	SCV000216655	likely benign	Hereditary cancer-predisposing syndrome	2019-02-28	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.
GeneDx	RCV001705615	SCV000526567	likely benign	not provided	2018-05-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12531920, 15385441, 16518693, 27376475, 10923033, 25782689, 10882858, 27062684, 29435075, 33087888)
Color Diagnostics, LLC DBA Color Health	RCV000165900	SCV000688420	likely benign	Hereditary cancer-predisposing syndrome	2017-10-24	criteria provided, single submitter	clinical testing
Mendelics	RCV000031087	SCV001140561	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000031087	SCV001287308	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442663	SCV001361790	uncertain significance	not specified	2019-12-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3082C>T (p.Arg1028Cys) results in a non-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 2e-05 in 251110 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3082C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Klemp_2000, Coulet_2010, Azzollini_2016, Schenkel_2016) and endometrioid cancer (Garcia-Sanz_2016) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant has also been found as a homozygous variant in a patient with a history of chronic lymphatic leukemia and breast cancer, but who did not exhibit symptoms typical of Fanconi anemia, as would be expected in a homozygous patient if the variant were pathogenic (Bondavalli_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as likley benign (n=4) and uncertain significance (n=1) . Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Genetic Services Laboratory, University of Chicago	RCV000442663	SCV002065817	likely benign	not specified	2021-12-16	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000442663	SCV005090350	benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031087	SCV000053683	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031087	SCV000144629	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing