ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9380G>A (p.Trp3127Ter)

dbSNP: rs80359211
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031818 SCV000301386 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000131047 SCV000185977 pathogenic Hereditary cancer-predisposing syndrome 2022-03-23 criteria provided, single submitter clinical testing The p.W3127* pathogenic mutation (also known as c.9380G>A), located in coding exon 24 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9380. This changes the amino acid from a tryptophan to a stop codon within coding exon 24. This alteration has been identified in multiple individuals whose personal and/or family histories were concerning for hereditary breast and ovarian cancer syndrome (Juwle A et al. Med. Oncol. 2012 Dec;29:3272-81; Moran O et al. Breast Cancer Res. Treat. 2017 01;161:135-142; Tung N et al. Cancer. 2015 Jan;121:25-33; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485069 SCV000296586 pathogenic not provided 2021-03-24 criteria provided, single submitter clinical testing This nonsense variant causes the premature termination of BRCA2 protein synthesis. It has been reported in individuals with breast and/or ovarian cancer in the published literature (PMID: 29785135 (2018), 29470806 (2018), 27798748 (2017), 22752604 (2012)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031818 SCV000328119 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000485069 SCV000567862 pathogenic not provided 2020-10-16 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Juwle 2012, Ricci 2014, Kwong 2016, Moran 2017); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.9608G>A; This variant is associated with the following publications: (PMID: 26187060, 25256924, 25186627, 29470806, 17899372, 22752604, 24065114, 28152038, 27798748, 28281021, 29785135, 29446198, 32885271)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781092 SCV000918910 pathogenic Hereditary breast ovarian cancer syndrome 2024-04-04 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9380G>A (p.Trp3127X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251360 control chromosomes (gnomAD). c.9380G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Juwle_2012, Tung_2014, Wang_2014, Moran_2017, Shah_2018). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22752604, 27798748, 29785135, 25186627, 25256924). ClinVar contains an entry for this variant (Variation ID: 38235). Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000131047 SCV001354791 pathogenic Hereditary cancer-predisposing syndrome 2023-05-24 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 25 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 22752604, 25186627, 27798748, 29470806, 29785135, 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000781092 SCV001579491 pathogenic Hereditary breast ovarian cancer syndrome 2023-08-03 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 38235). This variant is also known as c.9608G>A. This premature translational stop signal has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 22752604, 25186627, 26187060, 27798748, 29470806). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp3127*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798058 SCV002041920 pathogenic Breast and/or ovarian cancer 2022-07-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000485069 SCV002048073 pathogenic not provided 2021-01-20 criteria provided, single submitter clinical testing The BRCA2 c.9380G>A; p.Trp3127Ter variant (rs80359211) has been reported in individuals with a personal history of breast cancer and in individuals with family history of hereditary breast and ovarian cancer (Rebbeck 2018, Tung 2015, Wang 2014). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 38235) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the BRCA2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated BRCA2 protein lacking the nuclear localization signal (Jeyasekharan 2013). Additionally, other truncating variants downstream are considered pathogenic (Variation IDs: 52826, 52888, 38260, 52831). Based on available information, this variant is considered pathogenic. References: Jeyasekharan AD et al. A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Nat Struct Mol Biol. 2013 Oct;20(10):1191-8. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. Wang ET et al. BRCA1 germline mutations may be associated with reduced ovarian reserve. Fertil Steril. 2014 Dec;102(6):1723-8.
Baylor Genetics RCV003473232 SCV004210450 pathogenic Familial cancer of breast 2022-11-14 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000031818 SCV004846163 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2023-07-19 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 25 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 22752604, 25186627, 27798748, 29470806, 29785135, 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000485069 SCV005414170 pathogenic not provided 2024-02-05 criteria provided, single submitter clinical testing PM2, PM5_strong, PVS1
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000031818 SCV005437124 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2024-12-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp3127*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product.This premature translational stop signal has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 22752604, 25186627, 26187060, 27798748, 29470806). ClinVar contains an entry for this variant (Variation ID: 38235). This variant is also known as c.9608G>A. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031818 SCV000054426 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2010-04-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031818 SCV000147624 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355462 SCV001550355 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Trp3127X variant was identified in 1 of 200 proband chromosomes (frequency: 0.005) from individuals or families with early onset and sporadic breast cancer, and was not identified in 100 control chromosomes from healthy individuals (Juwle 2012).The variant was also identified in dbSNP (ID: rs80359211) as “With Pathogenic allele”; ClinVar and Clinvitae database (Pathogenic by Ambry Genetics, Sharing Clinical Reports Projects of Myriad, Breast Cancer Information Core (BIC), Quest Diagnostics, Nichols Institute, San Juan, Capistrano. Invitae did not provide a classification); Fanconi Anemia Mutation Database (LOVD) (1x classified deleterious); BIC database (5X class 5 causal with clinical importance); BRCA Share UMD (1X “causal” classification p.Trp3127X by c.9381A>G). The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a 3’ splice site; this is not very predictive of pathogenicity. Exonic splicing enhancers (ESE) studies indicate the effect on ESE is decreased. This may adversely affect splicing and thereby contribute to BRCA2 disruption (Pettigrew 2008).The p.Trp3127X variant leads to a premature stop codon at position 3127 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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