ClinVar Miner

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

gnomAD frequency: 0.01054  dbSNP: rs2227945
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Total submissions: 33
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen RCV000112092 SCV004101423 benign Breast-ovarian cancer, familial, susceptibility to, 1 2023-10-10 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 2023-09-01 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

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