Submissions for variant NM_000059.4(BRCA2):c.7525dup (p.Ser2509fs)

dbSNP: rs80359656

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000076998	SCV000301172	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.
Counsyl	RCV000076998	SCV000488461	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000486010	SCV000571248	pathogenic	not provided	2022-11-16	criteria provided, single submitter	clinical testing	Frameshift 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 7753dup; Observed in two individuals from a cohort in which most individuals had a personal history of breast or ovarian cancer (Herzog et al., 2021); This variant is associated with the following publications: (PMID: 34413315)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486010	SCV000600752	pathogenic	not provided	2021-05-04	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has not been reported in the published literature. It also 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	RCV000580386	SCV000683883	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-02	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 15 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least two individuals affected with breast cancer (doi: 10.20944/preprints202008.0718.v1; Color internal data). 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	RCV000588389	SCV000695075	likely pathogenic	Hereditary breast ovarian cancer syndrome	2017-05-26	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.7525dupA (p.Ser2509Lysfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g. c.7543dupA, p.Thr2515fs). One in silico tool predicts a damaging outcome for this variant. The variant of interest has not been found in a large, broad control population, ExAC in 120960 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000588389	SCV000759218	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser2509Lysfs*30) 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 clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 91481). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000580386	SCV001188924	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-13	criteria provided, single submitter	clinical testing	The c.7525dupA variant, located in coding exon 14 of the BRCA2 gene, results from a duplication of A at nucleotide position 7525, causing a translational frameshift with a predicted alternate stop codon (p.S2509Kfs*30). 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.
Sharing Clinical Reports Project (SCRP)	RCV000076998	SCV000108795	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-14	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000076998	SCV000147113	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing