Submissions for variant NM_000059.4(BRCA2):c.5482_5486del (p.Lys1828fs)

dbSNP: rs80359516

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083118	SCV000300881	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.
Ambry Genetics	RCV000162924	SCV000213411	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-01	criteria provided, single submitter	clinical testing	The c.5482_5486delAAATT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 5482 to 5486, causing a translational frameshift with a predicted alternate stop codon (p.K1828Vfs*4). This mutation was reported in a 56 year old Japanese female who underwent exome analysis as a subject ascertained for atherosclerosis phenotypes; she did not meet cancer family history based referral criteria (Johnston JJ, Am. J. Hum. Genet. 2012 Jul; 91(1):97-108). This alteration has also been reported as a pathogenic mutation in cohorts of East Asian individuals (Kwong A et al. J. Med. Genet., 2016 Jan;53:15-23; Momozowa Y et al. Nat Commun 2018 10;9(1):4083). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083118	SCV000327223	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034446	SCV001338526	pathogenic	Hereditary breast ovarian cancer syndrome	2020-04-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5482_5486delAAATT (p.Lys1828ValfsX4) 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 251050 control chromosomes (gnomAD). c.5482_5486delAAATT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Kwong_2016, Momozawa_2018, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have cited this variant (after 2014) as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034446	SCV001588705	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1828Valfs*4) 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 cancer (PMID: 26187060, 30287823). ClinVar contains an entry for this variant (Variation ID: 41553). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003473251	SCV004212862	pathogenic	Familial cancer of breast	2022-01-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162924	SCV004362108	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-18	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 individuals affected with breast cancer (PMID: 11149425, 26187060, 30287823). 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.
All of Us Research Program, National Institutes of Health	RCV000083118	SCV004846583	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-08	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 individuals affected with breast cancer (PMID: 11149425, 26187060, 30287823). 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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034446	SCV000043213	pathogenic	Hereditary breast ovarian cancer syndrome	2012-07-13	no assertion criteria provided	research	Converted during submission to Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000083118	SCV000115192	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083118	SCV000146623	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	RCV000034446	SCV000587771	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353701	SCV000591972	pathogenic	not provided		no assertion criteria provided	clinical testing	The p.Lys1828ValfsX4 variant was identified in the literature in a French family with hereditary breast or ovarian cancer (Lecarpentier 2012). The variant was also identified in the GeneInsight COGR database (classified as pathogenic by a clinical laboratory); UMD (2X, classified as “causal”); the BIC database (4X, with clinical significance), and the ClinVar database (classified as pathogenic by the Biesecker Laboratory - ClinSeq Project, Sharing Clinical Reports Project, BIC, and Ambry Genetics). The p.Lys1828ValfsX4 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1828 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Laboratory for Genotyping Development, RIKEN	RCV003162292	SCV002758432	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research