Submissions for variant NM_007294.4(BRCA1):c.3418A>G (p.Ser1140Gly)

gnomAD frequency: 0.01054  dbSNP: rs2227945

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004566802	SCV004101423	benign	BRCA1-related cancer predisposition	2024-06-11	reviewed by expert panel	curation	The c.3418A>G variant in BRCA1 is a missense variant predicted to cause substitution of Serine by Glycine at amino acid 1140 (p.Ser1140Gly). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.03171 in the African/African-American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 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 0.06, 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 more than 10 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score 4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.00029 (based on Co-occurrence LR=0.00029), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 16014699). 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 (BA1, BP1_Strong, BS3, BS2, BP5_Very strong).
Invitae	RCV000048187	SCV000076200	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000112092	SCV000153996	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-01-02	criteria provided, single submitter	literature only
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112092	SCV000195920	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120277	SCV000202267	benign	not specified	2014-03-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162594	SCV000213012	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.
Illumina Laboratory Services, Illumina	RCV000112092	SCV000403060	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-02-22	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048187	SCV000494372	benign	Hereditary breast ovarian cancer syndrome	2013-10-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477058	SCV000575714	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-10-21	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000048187	SCV000576441	likely benign	Hereditary breast ovarian cancer syndrome	2017-02-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034741	SCV000602707	benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162594	SCV000683103	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000112092	SCV000744635	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120277	SCV000806933	benign	not specified	2017-05-05	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197692	SCV001368471	benign	Familial cancer of breast	2018-09-25	criteria provided, single submitter	clinical testing	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000048187	SCV002025956	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000048187	SCV002515197	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162594	SCV002538206	benign	Hereditary cancer-predisposing syndrome	2020-03-26	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120277	SCV002550999	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149613	SCV003838901	benign	Breast and/or ovarian cancer	2021-07-06	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000112092	SCV004016762	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034741	SCV004041995	benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	BRCA1: BP4, BS1, BS2
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034741	SCV000043167	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000120277	SCV000084429	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112092	SCV000144758	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Medical Genetics, University Hospital of North Norway	RCV000112092	SCV000301433	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120277	SCV000591444	benign	not specified		no assertion criteria provided	clinical testing	The BRCA1, c.3418A>G, p.Ser1140Gly variant has been reported in the literature in at least 18/44788 proband chromosomes of individuals with sporadic as well as high-risk breast and /or ovarian cancer. It has also been found in 4/5118 control chromosomes evaluated (Tavtigian_2006_16014699, Abkevich_2004_15235020, Johnson_2007_17341484, McKean-Cowdin_2005_15726418, Alsop_2012_22711857, Elstrodt_2006_16397213, Tazzite_2012_22425665, Velasco_2005_15937982, Soegaard_2008_18559594). It is listed in the dbSNP database (ID#: rs2227945) as coming from a clinical source with a minor allele frequency of 0.011, having been observed in 25 chromosomes (1000 genomes), increasing the likelihood that this is benign variant. It has been listed in the UMD (x14 as neutral), BIC (x29 as UV) and the CNPHI (ACMG 3) databases. In addition, in the UMD mutation database, the variant was observed to co-occur with pathogenic BRCA1 [c.2890G>T (p.Gly964X) and c.415C>T (p.Gln139X)] as well as BRCA2 [c.2092delC (p.Leu698TyrfsX32)] variants, increasing the likelihood that p.Ser1140Gly is benign. This residue is not conserved in mammals and the variant amino acid Glycine (Gly) is present in the mouse. Computational analyses (PolyPhen, SIFT, AlignGVGD) does not predict any effect on the protein function, increasing the likelihood this variant does not have functional significance. In summary, based on the above information, this variant is classified as Benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000034741	SCV000778747	benign	not provided	2017-10-09	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162594	SCV000787902	benign	Hereditary cancer-predisposing syndrome	2018-01-03	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120277	SCV001906218	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000120277	SCV001927092	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120277	SCV001953692	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112092	SCV004244044	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing