Submissions for variant NM_007294.4(BRCA1):c.3823A>G (p.Ile1275Val)

gnomAD frequency: 0.00011  dbSNP: rs80357280

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031130	SCV001161512	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 4.02E-06
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195318	SCV000076359	benign	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000034745	SCV000209962	likely benign	not provided	2021-03-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31131967, 30400234, 30254663, 30263092, 22703879, 26580448, 21520273, 22476429, 21120943, 2693380, 24728327, 16267036, 28508593, 18824701, 15235020, 21990134, 27741520, 27616075, 20104584, 26543556, 19471317, 17924331, 22753008, 23961350)
Ambry Genetics	RCV000162522	SCV000212917	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Eurofins Ntd Llc (ga)	RCV000034745	SCV000224999	uncertain significance	not provided	2015-04-22	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000195318	SCV000258061	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-02-05	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031130	SCV000743399	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031130	SCV000744622	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162522	SCV000910633	benign	Hereditary cancer-predisposing syndrome	2015-11-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000031130	SCV001140541	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000120279	SCV001158790	likely benign	not specified	2019-01-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034745	SCV001247352	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	BRCA1: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120279	SCV001338472	benign	not specified	2021-08-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3823A>G (p.Ile1275Val) results in a conservative amino acid change in 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 0.00017 in 251142 control chromosomes, predominantly at a frequency of 0.0009 within the Latino subpopulation in the gnomAD database. This frequency is similar to the estimated maximum allele frequency expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (0.0009 vs 0.001), suggesting that this variant could be a rare benign polymorphism found predominantly in populations of Latino origin. c.3823A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome, however without strong evidence for causality (example: Judkins_2005, Spearman_2008, Caux-Moncoutier_2009, Borg_2010, Lu_2012, Solano_2013, Dean_2015, Fernandes_2016, Kraus_2017, Brianese_2018, Germani_2018, Diaz-Zabala_2018, Zuntini_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.8364G>A, p.Trp2788X in UMD database; BRCA2 c.3922G>T, p.Glu1308X in BIC database; BRCA2 c.9672dupA, p.Tyr3225fs in internal database), providing supporting evidence for a benign role. Several publications investigating the variant effect in-vitro reported no impact on splicing or allelic imbalance (example: Anczukow_2008, Caux-Montcoutier_2009), however to our knowledge, no experimental evidence evaluating an impact on protein function has been reported. Eleven other ClinVar submitters (evaluation after 2014) including an expert panel (ENIGMA) cite the variant as benign/likely benign (n=9) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000120279	SCV002068657	likely benign	not specified	2019-03-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162522	SCV002538247	likely benign	Hereditary cancer-predisposing syndrome	2021-04-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120279	SCV004026771	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000034745	SCV005251055	benign	not provided		criteria provided, single submitter	not provided
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034745	SCV000043163	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP)	RCV000031130	SCV000053729	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2008-11-12	no assertion criteria provided	clinical testing
ITMI	RCV000120279	SCV000084431	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031130	SCV000144888	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120279	SCV001951628	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554627	SCV004755657	likely benign	BRCA1-related disorder	2020-03-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).