Submissions for variant NM_000059.4(BRCA2):c.8434GGA[1] (p.Gly2813del)

dbSNP: rs397507986

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003476933	SCV004220605	uncertain significance	not provided	2023-09-14	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 34645131 (2022), 16949048 (2006)) and ovarian cancer (PMID: 26402875 (2015)). This variant has also been reported in an unaffected individual (PMID: 32467295 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, we are unable to determine the clinical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003529944	SCV004297186	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-08	criteria provided, single submitter	clinical testing	This variant, c.8437_8439del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Gly2813del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features consistent with hereditary breast and ovarian cancer syndrome (PMID: 16949048, 26402875, 29240602, 34645131). This variant is also known as 8665_8667delGGA; c.8662delGGA. ClinVar contains an entry for this variant (Variation ID: 52588). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV003584521	SCV004362749	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid in the DNA-binding domain of the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 29240602, 34645131). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003476933	SCV004848573	uncertain significance	not provided	2021-11-09	criteria provided, single submitter	clinical testing	The p.Gly2813del variant in BRCA2 has been reported in 3 individuals with breast or ovarian cancer and segregated with disease in 1 affected relative (Kim 2006 PMID: 16949048, Choi 2015 PMID: 26402875, Gao 2020 PMID: 31825140). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 52588). This variant is a deletion of 1 amino acid at position 2813 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM2_Supporting, PM4_Supporting.
Ambry Genetics	RCV003584521	SCV005030917	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-30	criteria provided, single submitter	clinical testing	The c.8437_8439delGGA variant (also known as p.G2813del) is located in coding exon 18 of the BRCA2 gene. This variant results from an in-frame GGA deletion at nucleotide positions 8437 to 8439. This results in the in-frame deletion of a glycine at codon 2813. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Han SH et al. Clin Genet, 2006 Dec;70:496-501; Kim BY et al. Biochem Biophys Res Commun, 2006 Oct;349:604-10; Choi MC et al. Int J Gynecol Cancer, 2018 Feb;28:308-315). Of note, this alteration is also known as 8662delGGA in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577291	SCV000679002	not provided	Familial cancer of breast		no assertion provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356920	SCV001552211	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Gly2813del variant was identified in 2 of 2180 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer and was not identified in 334 control chromosomes from healthy individuals (Kim 2006, Choi 2018). The variant was also identified in dbSNP (ID: rs397507986, as “With untested allele”), in ClinVar (clinical significance not provided), and ARUP Laboratories (as Definitely pathogenic) databases. The variant was not identified in GeneInsight-COGR, Clinvitae, Cosmic, LOVD 3.0, UMD-LSDB, BIC Database, or Zhejiang University Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). One study identified the variant in a Korean patient with ovarian cancer as well as in her sister who had breast cancer demonstrating co-segregation of the variant albeit only in 2 family members tested (Choi 2018). This variant is an in-frame deletion resulting in the removal of a glycine (gly) residue at codon 2813; the impact of this alteration on BRCA2 protein function is not known. Although in silico protein prediction algorithms are not designed to predict the functioneffect of in-frame deletions the p.Gly2813 reside is well conserved across many species. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.