Submissions for variant NM_000059.4(BRCA2):c.4965C>A (p.Tyr1655Ter)

dbSNP: rs80358721

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083111	SCV000300808	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083111	SCV000327114	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000083111	SCV000743302	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000496256	SCV000838802	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758902	SCV000887831	pathogenic	not provided	2023-05-22	criteria provided, single submitter	clinical testing	This variant causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals and families with breast and/or ovarian cancer (PMIDs: 33471991 (2021), 29446198 (2018), 30287823 (2018), 25136594 (2014)). 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.
Color Diagnostics, LLC DBA Color Health	RCV001175640	SCV001339318	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	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.
Invitae	RCV000496256	SCV001578004	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1655*) 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 and/or ovarian cancer (PMID: 17688236, 20858050, 21120943, 21709188, 23569316, 24728189, 25136594, 26681312, 29446198, 29487695). ClinVar contains an entry for this variant (Variation ID: 51750). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000758902	SCV001789418	pathogenic	not provided	2022-12-21	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 BRCA2-related cancers (Sakai 2009, Caux-Moncoutier 2011); Published functional studies support a damaging effect: sensitivity to cisplatin (Sakai 2009); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); Also known as 5193C>A; This variant is associated with the following publications: (PMID: 25136594, 19654294, 21120943, 25525159, 29446198, 21205087, 30287823, 32377563, 33087929)
Ambry Genetics	RCV001175640	SCV002645762	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	The p.Y1655* pathogenic mutation (also known as c.4965C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 4965. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. In one study, this variant was observed in 1/1525 unrelated patients who had BRCA1/2 genetic testing due to a personal and/or family history suspicious for Hereditary Breast and/or Ovarian Cancer (Caux-Moncoutier V et al. Hum. Mutat., 2011 Mar;32:325-34). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620) and has been reported with a carrier frequency of 0.00014 in 7051 unselected breast cancer patients and 0.00000 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335075	SCV004046144	pathogenic	FLG-related disorders		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 11 of 28 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported as a heterozygous change in patients with BRCA2-related cancers (PMID: 17688236, 19654294, 20858050, 21709188, 23569316, 24728189, 25136594, 26681312, 28973083, 29371908). Loss-of-function variation in BRCA2 is an established mechanism of disease (ClinVar; HGMD Database). The c.4965C>A (p.Tyr1655Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.4965C>A (p.Tyr1655Ter) variant is classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000758902	SCV004132986	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2
Baylor Genetics	RCV003460588	SCV004213618	pathogenic	Familial cancer of breast	2023-09-02	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083111	SCV000115185	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-10-12	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083111	SCV000146513	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-07-11	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496256	SCV000587735	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000083111	SCV000733259	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000758902	SCV001906146	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000083111	SCV002588880	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing