Submissions for variant NM_000059.4(BRCA2):c.4222C>T (p.Gln1408Ter)

dbSNP: rs80358663

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)	RCV000031470	SCV000300724	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044373	SCV000072386	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1408*) 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 cancer (PMID: 19818148, 22009639). This variant is also known as 4450C>T. ClinVar contains an entry for this variant (Variation ID: 37889). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000215029	SCV000274248	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	clinical testing	The p.Q1408* pathogenic mutation (also known as c.4222C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 4222. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Miolo G et al. BMC Cancer, 2009 Oct;9:360; Bayraktar S et al. Cancer 2012 Mar; 118(6):1515-22; Cardoso FC et al. Hum Genomics, 2018 08;12:39). Additionally, this alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note this alteration is also described in the literature as 4450C>T. 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	RCV000031470	SCV000326991	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000480509	SCV000567660	pathogenic	not provided	2023-08-02	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 breast and/or ovarian cancer (Miolo et al., 2009; Bayraktar et al., 2012; Cardoso et al., 2018; Liang et al., 2018); 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; Also known as 4450C>T; This variant is associated with the following publications: (PMID: 30787465, 19818148, 22009639, 29681614, 29446198, 30103829, 29907814, 28888541, 32377563, 36556183, 34308104)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480509	SCV000600581	pathogenic	not provided	2022-08-19	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 30103829 (2018), 29907814 (2018), 28888541 (2017), 22009639 (2012), 20104584 (2010), 19818148 (2009)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044373	SCV000694754	pathogenic	Hereditary breast ovarian cancer syndrome	2020-08-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4222C>T (p.Gln1408X) 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 240092 control chromosomes. c.4222C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Bayraktar_2012, Miolo_2009, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories and one expert panel (ENIGMA) 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.
Color Diagnostics, LLC DBA Color Health	RCV000215029	SCV000903057	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-21	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 been reported in individuals affected with breast cancer and ovarian cancer (PMID: 19818148, 22009639, 34072659). 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.
Revvity Omics, Revvity	RCV000480509	SCV003813828	pathogenic	not provided	2022-04-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473172	SCV004212845	pathogenic	Familial cancer of breast	2024-03-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031470	SCV004845284	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-10-31	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 been reported in 1 individual affected with ovarian cancer and 2 individuals affected with breast cancer (PMID: 19818148, 22009639, 34072659). This variant has been identified in 27 families among the CIMBA participants (PMID: 29446198). 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.
Sharing Clinical Reports Project (SCRP)	RCV000031470	SCV000054075	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-03-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031470	SCV000146393	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044373	SCV000587705	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004532442	SCV004711954	pathogenic	BRCA2-related disorder	2023-12-04	no assertion criteria provided	clinical testing	The BRCA2 c.4222C>T variant is predicted to result in premature protein termination (p.Gln1408*). This variant has been reported in an individual with ductal carcinoma in situ (Bayraktar et al. 2012. PubMed ID: 22009639), in an individual with ovarian cancer (Cardoso et al. 2018. PubMed ID: 30103829, Additional File 1), in an individual undergoing hereditary cancer testing (Palmero et al. 2018. PubMed ID: 29907814, Table 2), and is reported in multiple families from a BRCA1/2 consortium (Rebbeck et al. 2018. PubMed ID: 29446198, Table S1). This variant has not been reported in a large population database, indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37889). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.