Submissions for variant NM_000059.4(BRCA2):c.3873del (p.Gln1291fs)

dbSNP: rs398122772

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)	RCV000077717	SCV000300680	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	RCV000077717	SCV000326935	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496920	SCV000635316	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1291Hisfs*2) 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 skin cancer (PMID: 26023681). This variant is also known as 4101delA. ClinVar contains an entry for this variant (Variation ID: 91809). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758890	SCV000887804	pathogenic	not provided	2022-02-14	criteria provided, single submitter	clinical testing	This frameshift 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 large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast and skin cancer (PMID: 26023681 (2015)), ovarian cancer (PMID: 24728189 (2014)), and pancreatic cancer (PMID: 29945567 (2018)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001184521	SCV001350513	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4101delA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast, ovarian, and pancreatic cancer (PMID: 24728189, 26023681, 29945567, 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	RCV000496920	SCV002512016	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-25	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3873delA (p.Gln1291HisfsX2) 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 194150 control chromosomes. c.3873delA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV001184521	SCV002624869	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-08	criteria provided, single submitter	clinical testing	The c.3873delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 3873, causing a translational frameshift with a predicted alternate stop codon (p.Q1291Hfs*2). In one case control study, this mutation was detected in 1/2222 individuals with invasive epithelial ovarian cancer and 0/1528 matched controls (Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9). Another study identified this mutation, referred to as 4101delA, in a female patient diagnosed with breast cancer at ages 28, 39, and 55 then with skin cancer at age 55 (Foley SB et al. EBioMedicine, 2015 Jan;2:74-81). This mutation has also been detected in a patient with pancreatic cancer (Young EL et al. BMC Cancer, 2018 Jun;18:697). 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.
Baylor Genetics	RCV003474667	SCV004210440	pathogenic	Familial cancer of breast	2023-12-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496920	SCV004847919	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Gln1291HisfsX2 variant in BRCA2 (also referred to in the literature as c.4101delA) has been reported in at least 3 individuals with BRCA2-related cancers (Young 2018, Song 2014, Foley 2015). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1291 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 91809). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.
Sharing Clinical Reports Project (SCRP)	RCV000077717	SCV000109520	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-10-25	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496920	SCV000587686	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000758890	SCV001552850	uncertain significance	not provided		no assertion criteria provided	clinical testing