Submissions for variant NM_000059.4(BRCA2):c.4058_4062del (p.Glu1353fs)

dbSNP: rs397507322

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)	RCV000031456	SCV000300703	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	RCV000198983	SCV000255249	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1353Glyfs*6) 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 present in population databases (rs397507322, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21318380). This variant is also known as c.4057_4061del5 and 4286del5. ClinVar contains an entry for this variant (Variation ID: 37875). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000223041	SCV000278848	pathogenic	not provided	2025-02-12	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 25186627, 29446198); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4286_4290delAAACG; This variant is associated with the following publications: (PMID: 25186627, 21318380, 29446198, 30720243, 20104584)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031456	SCV000326965	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031456	SCV000489640	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-11-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000198983	SCV000694738	pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4058_4062delAAACG (p.Glu1353GlyfsX6) 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. Multiple truncations downstream of this position have been classified as pathogenic by our laboratory (example c.4092_4093delAT [p.Ile1364fsX3], c.4111C>T [p.Gln1371X], and c.4133_4136delCTCA [p.Thr1378fsX9]). The variant was absent in 241134 control chromosomes (gnomAD). c.4058_4062delAAACG has been reported in the literature in individuals affected with and a family history of breast and/or ovarian cancers (example Tung_2014, Rebbeck_2018). These data indicate that the variant is likely with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical-significance assessments for this variant have been submitted to ClinVar after 2014. Seven submitters classified the variant as pathogenic and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000772117	SCV000905180	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-27	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides in exon 11 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 one individual affected with breast cancer, over the age of 50 at the time of diagnosis, with a family history of breast cancer (PMID: 25186627) and has been identified in 1 family 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.
Ambry Genetics	RCV000772117	SCV001183422	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-26	criteria provided, single submitter	clinical testing	The c.4058_4062delAAACG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 4058 to 4062, causing a translational frameshift with a predicted alternate stop codon (p.E1353Gfs*6). This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). 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). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000223041	SCV002046159	pathogenic	not provided	2021-04-10	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast cancer in the published literature (PMID: 21318380 (2011), 25186627 (2015), 29446198 (2018)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV003460508	SCV004213646	pathogenic	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031456	SCV000054061	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-10-23	no assertion criteria provided	clinical testing