Submissions for variant NM_000059.4(BRCA2):c.250C>T (p.Gln84Ter)

dbSNP: rs80358515

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)	RCV000077281	SCV000282368	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195353	SCV000072020	pathogenic	Hereditary breast ovarian cancer syndrome	2024-09-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln84*) 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 breast, ovarian and prostate cancer (PMID: 18445692, 20807450, 20858050, 21939546, 22970155). This variant is also known as 478C>T. ClinVar contains an entry for this variant (Variation ID: 51298). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000044007	SCV000210438	pathogenic	not provided	2024-06-12	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 (PMID: 20807450, 21939546, 22970155, 28294317); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 478C>T; This variant is associated with the following publications: (PMID: 18445692, 26586665, 20858050, 26681312, 28294317, 29446198, 30702160, 20807450, 21939546, 22970155, 34399810, 30720863, 31825140, 31090900, 30787465, 20104584, 34887416, 37310942, 30145549, 31853058, 35216584)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000044007	SCV000296646	pathogenic	not provided	2021-01-19	criteria provided, single submitter	clinical testing	his nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in families affected with prostate cancer or breast/ovarian cancer in the published literature (PMID: 18445692 (2008), 21939546 (2011), 29446198 (2018), 30702160 (2019)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . 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	RCV000077281	SCV000326715	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564855	SCV000665934	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-13	criteria provided, single submitter	clinical testing	The p.Q84* pathogenic mutation (also known as c.250C>T), located in coding exon 2 of the BRCA2 gene, results from a C to T substitution at nucleotide position 250. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This mutation has been reported in multiple individuals and families with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Willems AJ et al. Clin. Cancer Res., 2008 May;14:2953-61; Turkovic L et al. BMC Cancer, 2010;10:466; Coulet F et al. Genet Test Mol Biomarkers, 2010 Oct;14:677-90; Muller D et al. BMC Med. Genet., 2011 Sep;12:121; Kwong A et al. PLoS ONE, 2012 Sep;7:e43994; Susswein LR et al. Genet Med, 2016 08;18:823-32; Lang GT et al. Int J Cancer, 2017 07;141:129-142; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Nguyen-Dumont T et al. BMC Cancer, 2018 02;18:165; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; Nones K et al. Ann Oncol, 2019 07;30:1071-1079). 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.
Color Diagnostics, LLC DBA Color Health	RCV000564855	SCV000903712	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-04	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals at high-risk for breast and/or ovarian cancer (PMID: 21939546, 22970155) and in an individual affected with prostate cancer from a family with multiple cases of breast cancer (PMID: 18445692). 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	RCV000195353	SCV001774610	pathogenic	Hereditary breast ovarian cancer syndrome	2021-08-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.250C>T (p.Gln84X) 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. The variant was absent in 251326 control chromosomes. c.250C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All sumbitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003473315	SCV004212889	pathogenic	Familial cancer of breast	2021-10-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000195353	SCV004847696	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-02	criteria provided, single submitter	clinical testing	The p.Gln84X variant in BRCA2 has been reported in >10 individuals with BRCA2-related cancers, as well as in one man with prostate cancer (Willems 2008, Turkovic 2010, Kwong 2012, Lang 2017, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 84, 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 HBOC. In addition, this variant was classified as Pathogenic by the ClinGen-approved ENIGMA expert panel (Variation ID: 51298). 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)	RCV000077281	SCV000109078	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-01-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077281	SCV000146448	not provided	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000195353	SCV000587543	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000077281	SCV004243692	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004724776	SCV005338598	pathogenic	BRCA2-related disorder	2024-05-06	no assertion criteria provided	clinical testing	The BRCA2 c.250C>T variant is predicted to result in premature protein termination (p.Gln84*). This variant is also referred to as c.478C>T in literature. It has been reported in several individuals with breast or prostate cancer (see for example, Willems et al. 2008. PubMed ID: 18445692; Table S3, Lang et al. 2017. PubMed ID: 28294317; Table 2, Murali et al. 2021. PubMed ID: 34399810). It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51298/). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.