Submissions for variant NM_000059.4(BRCA2):c.961C>T (p.Gln321Ter)

dbSNP: rs80359234

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112867	SCV000300376	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	RCV000217571	SCV000275365	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-06	criteria provided, single submitter	clinical testing	The p.Q321* pathogenic mutation (also known as c.961C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 961. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration has been identified in a woman diagnosed with breast cancer at age 40 with two relatives with breast cancer under age 50 (Frank TS et al. J. Clin. Oncol. 1998 Jul; 16(7):2417-25). Of note, this alteration is also known as 1189C>T in published literature. 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	RCV000112867	SCV000328158	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000217571	SCV000689212	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 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.
GeneDx	RCV000657627	SCV000779370	pathogenic	not provided	2018-02-01	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.961C>T at the cDNA level and p.Gln321Ter (Q321X) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 1189C>T. This substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual with colon cancer, multiple individuals with breast cancer, and in at least one individual with a personal and family history of breast cancer (Frank 1998, Adem 2003, Spearman 2008, Dworkin 2009, Pearlman 2017, Sun 2017). BRCA2 Gln321Ter is considered pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496598	SCV001338584	pathogenic	Hereditary breast ovarian cancer syndrome	2020-04-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.961C>T (p.Gln321X) 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 227608 control chromosomes. c.961C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (eg. Rebbeck_2018, Frank_1998, Chaffee_2018, Bhaskaran_2019). 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. Five 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496598	SCV001587952	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln321*) 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, colon, or pancreatic cancer (PMID: 9667259, 27978560, 28724667, 28726808). ClinVar contains an entry for this variant (Variation ID: 52876). For these reasons, this variant has been classified as Pathogenic.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000496598	SCV002819238	pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460634	SCV004214554	pathogenic	Familial cancer of breast	2021-08-01	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112867	SCV000145795	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	RCV000496598	SCV000587576	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research