Submissions for variant NM_000059.4(BRCA2):c.5410_5411del (p.Val1804fs)

dbSNP: rs80359512

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031544	SCV000300872	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	RCV000044655	SCV000072668	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val1804Lysfs*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/or ovarian cancer (PMID: 15340362, 24963353). This variant is also known as 5638delGT. ClinVar contains an entry for this variant (Variation ID: 37963). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131109	SCV000186039	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	clinical testing	The c.5410_5411delGT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 5410 to 5411, causing a translational frameshift with a predicted alternate stop codon (p.V1804Kfs*2). This alteration has been identified in several breast/ovarian cohorts and in a 56-year-old Australian female with pancreatic cancer (Marroni F et al. Eur. J. Hum. Genet. 2004 Nov;12(11):899-906; Johns A et al. Genome Med. 2014 May 29;6(5):42; Meeks HD et al. J. Natl. Cancer Inst. 2016 Feb;108(2); Dougherty BA et al. Oncotarget, 2017 Jul;8:43653-43661). 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). Of note, this alteration is also designated as 5638delGT in published literature. 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.
GeneDx	RCV000219181	SCV000278860	pathogenic	not provided	2023-12-18	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; Observed in individuals with personal or family history of BRCA2-related cancers (PMID: 12048272, 15340362, 24963353, 26586665); 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 5638delGT or 5638_5639delGT; This variant is associated with the following publications: (PMID: 15340362, 34657373, 31447099, 26586665, 24963353, 12048272, 32194909, 30787465)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031544	SCV000327215	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044655	SCV000605822	pathogenic	Hereditary breast ovarian cancer syndrome	2017-07-20	criteria provided, single submitter	clinical testing	The p.Val1804fs variant in BRCA2 has been reported in 6 individuals with heredit ary breast and/or ovarian cancer (HBOC; Marroni 2004, Breast Cancer Information Core (BIC) database; https://research.nhgri.nih.gov/projects/bic/) and was absen t from large population studies, though the ability of these studies to accurate ly detect indels may be limited. This variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning at position 1804 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss o f function of the BRCA2 gene is an established disease mechanism in HBOC. In add ition, this variant was classified as pathogenic on Sept 8, 2016 by the ClinGen- approved ENIGMA expert panel (ClinVar SCV000300872.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based on predicted impact to the protein and absence from controls.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044655	SCV000694866	pathogenic	Hereditary breast ovarian cancer syndrome	2022-05-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5410_5411delGT (p.Val1804LysfsX2) 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 251140 control chromosomes. c.5410_5411delGT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000219181	SCV000889067	pathogenic	not provided	2021-05-12	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. It 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 cancer, pancreatic cancer, and ovarian cancer (PMIDs: 33888336 (2021), 32563252 (2020), 32194909 (2020), 29446198 (2018), 28525389 (2017), 24963353 (2014)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131109	SCV000911345	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-21	criteria provided, single submitter	clinical testing	This variant deletes 2 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 detected in 2 individuals affected with ovarian cancer (PMID: 28525389, 33888336), 2 individuals affected with pancreatic cancer (PMID: 24963353, 32194909), an individual from a cohort affected with BRCA-associated cancer (PMID: 32699032), in a suspected hereditary breast and ovarian cancer family (PMID: 15340362), and in 20 families 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000219181	SCV001716157	pathogenic	not provided	2020-11-16	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000044655	SCV004046036	pathogenic	Hereditary breast ovarian cancer syndrome		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 11 of 28 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with breast and/or ovarian cancer (PMID: 15340362, 12048272, 28525389) and pancreatic cancer (PMID: 24963353). This variant is also known as 5638delGT in the literature. It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.5410_5411del (p.Val1804LysfsTer2) variant is classified as Pathogenic.
Baylor Genetics	RCV003473188	SCV004210432	pathogenic	Familial cancer of breast	2024-03-21	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031544	SCV000054149	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2007-11-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031544	SCV000146609	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044655	SCV000587766	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735564	SCV000863702	pathogenic	Breast and/or ovarian cancer	2010-06-28	no assertion criteria provided	clinical testing