Submissions for variant NM_000059.4(BRCA2):c.1414C>T (p.Gln472Ter)

dbSNP: rs80358429

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112920	SCV000300429	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	RCV000043802	SCV000071815	pathogenic	Hereditary breast ovarian cancer syndrome	2020-08-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has been observed in individuals with high risk of breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 51121). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln472*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112920	SCV000326553	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509751	SCV000608124	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-29	criteria provided, single submitter	clinical testing	The p.Q472* pathogenic mutation (also known as c.1414C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1414. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV000657753	SCV000779505	pathogenic	not provided	2023-05-04	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; Also known as 1642C>T; This variant is associated with the following publications: (PMID: 30787465, 33558524, 31409081, 32377563, 35753294, 29446198, Bahsi2019[article], 32776218, 35171259, 32658311)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043802	SCV002051261	pathogenic	Hereditary breast ovarian cancer syndrome	2021-12-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1414C>T (p.Gln472X) also know as HGVS 1642C>T 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 247704 control chromosomes (gnomAD). c.1414C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Moradian_2021, Akcay_2020, Sokolenko_2020, Machackova_2019 and Rebbeck_BRCA1_2018). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories and and expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV002514185	SCV004212842	pathogenic	Familial cancer of breast	2022-02-15	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112920	SCV000145869	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV000043802	SCV000987240	pathogenic	Hereditary breast ovarian cancer syndrome	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria The BRCA2 variant p.Gln472Ter is a known pathogenic variant in exon 10 and in a non- functional domain. This nonsense variant truncates the protein and thus makes it non-functional which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This variant was observed in a mutation hotspot region of 20 pathogenic variants (source, ClinVar) (PM1 Pathogenic Moderate). The variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300429.2) (PP5 Pathogenic Supporting). In this study this variant was found in a 53-year-old female with unilateral breast cancer and a strong family history. Therefore, this variant was classified as a Pathogenic.
CZECANCA consortium	RCV001270984	SCV001451794	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554325	SCV001775494	pathogenic	Breast carcinoma	2021-08-09	no assertion criteria provided	clinical testing
Research and Experiment Center, Meizhou People's Hospital	RCV002514185	SCV003760907	pathogenic	Familial cancer of breast		no assertion criteria provided	clinical testing