Submissions for variant NM_000059.4(BRCA2):c.3158T>G (p.Leu1053Ter)

gnomAD frequency: 0.00001  dbSNP: rs41293477

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031401	SCV000282377	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000162916	SCV000213403	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-31	criteria provided, single submitter	clinical testing	The p.L1053* pathogenic mutation (also known as c.3158T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 3158. This changes the amino acid from a leucine to a stop codon within coding exon 10. This mutation has been detected in hereditary breast/ovarian cancer families (Lubinski J et al. Fam. Cancer 2004 ;3(1):1-10; Elimam AA et al. BMC Med. Genet. 2017 08;18(1):85) as well as in individuals with early-onset and/or familial prostate cancer (Kote-Jarai Z et al. Br. J. Cancer 2011 Oct;105(8):1230-4; Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031401	SCV000326818	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031401	SCV000489489	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000424640	SCV000517371	pathogenic	not provided	2022-05-17	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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal and/or family history of breast and/or prostate cancer, as well as in unaffected controls (Kote-Jarai 2011, Song 2014, Dobbins 2016, Elimam 2017, Mijuskovic 2018); Also known as 3386T>G; This variant is associated with the following publications: (PMID: 19329713, 29915322, 27356891, 15131399, 21952622, 25525159, 29339979, 29446198, 32853339, 33087929, 21702907, 20002770, 23569316, 27225637, 28814288, 24728189)
Department of Medical Genetics, Oslo University Hospital	RCV000031401	SCV000605657	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162916	SCV000683528	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-26	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496393	SCV000917039	pathogenic	Hereditary breast ovarian cancer syndrome	2018-10-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3158T>G (p.Leu1053X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.3166C>T, p.Gln1056X; c.3170_3174delAGAAA, p.Lys1057fsX8; c.3187C>T, p.Gln1063X). The variant was absent in 241474 control chromosomes (gnomAD). The variant, c.3158T>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lubinski_2004, Mitra_2009). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000424640	SCV001133739	pathogenic	not provided	2023-06-29	criteria provided, single submitter	clinical testing	The BRCA2 c.3158T>G (p.Leu1053*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in an affected individual with breast cancer (PMID: 28814288 (2017)), as well as in individuals with prostate cancer (PMIDs: 32853339 (2021), 29915322 (2018), 23569316 (2013), and 21952622 (2011)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496393	SCV001590791	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1053*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with prostate cancer and increased risk of breast and ovarian cancers (PMID: 21952622, 23524863, 23569316, 28814288, 29446198). This variant is also known as 3386T>G. ClinVar contains an entry for this variant (Variation ID: 37820). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003460504	SCV004216039	pathogenic	Familial cancer of breast	2023-07-08	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496393	SCV004848269	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Leu1053X variant in BRCA2 has been reported in at least 11 individuals with BRCA2-related cancers (Lubinski 2004, Kote-Jarai 2011, Elimam 2017, Mijuskovic 2018, Sandhu 2013, BIC database) and was absent from large population studies. This nonsense variant creates a premature termination codon at position 1053, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar Variation ID: 37820). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
Sharing Clinical Reports Project (SCRP)	RCV000031401	SCV000054006	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-05-31	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031401	SCV000146179	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496393	SCV000587658	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research