Submissions for variant NM_007294.4(BRCA1):c.3608G>A (p.Arg1203Gln)

gnomAD frequency: 0.00006  dbSNP: rs55930959

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112134	SCV000244343	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	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 = 0.00000365
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048252	SCV000076265	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162979	SCV000213467	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.
Pathway Genomics	RCV000112134	SCV000223747	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-30	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000048252	SCV000258060	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-07-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000112134	SCV000489044	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000588566	SCV000515531	likely benign	not provided	2020-10-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21990134, 20104584, 21218378, 18284688, 19471317, 21520273, 21120943, 15447980, 15235020, 25011685, 22753008, 17924331, 27376475, 25948282, 18273839, 15983021, 23704879, 16267036, 15385441, 33087888)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000428879	SCV000699045	benign	not specified	2021-07-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3608G>A (p.Arg1203Gln) 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 4.8e-05 in 251078 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.001), allowing no conclusion about variant significance. c.3608G>A has been widely reported in the literature in individuals undergoing sequence based analysis for Hereditary Breast And Ovarian Cancer Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability models have classified this variant as neutral/benign with an IARC classification of 1 (benign) (example, Easton_2007, Lindor_2012, Lyra_2021). At-least two co-occurrences with other pathogenic variant(s) have been reported in the BIC database and observed at our laboratory (BIC, BRCA2 c.778_779delGA, p.Glu260Serfs; Our lab, BRIP1 c.890delA, p.Lys297fs), providing supporting evidence for a benign role. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus leaning towards benign/likely benign (n=6). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000162979	SCV000903322	likely benign	Hereditary cancer-predisposing syndrome	2018-05-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588566	SCV001151330	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	BRCA1: BP1, BP4, BS2
Illumina Laboratory Services, Illumina	RCV000112134	SCV001284948	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000428879	SCV004026775	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588566	SCV004219362	benign	not provided	2023-07-21	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112134	SCV000144808	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+	RCV000588566	SCV001952096	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000428879	SCV001970811	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004554665	SCV004760324	likely benign	BRCA1-related disorder	2023-11-30	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).