Submissions for variant NM_000059.4(BRCA2):c.4415_4418del (p.Lys1472fs)

dbSNP: rs397507333

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031483	SCV000300744	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	RCV000044410	SCV000072423	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1472Thrfs*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 (rs748716604, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and breast and/or ovarian cancer (PMID: 15131399, 15918047, 24010542, 26681682, 28195393). ClinVar contains an entry for this variant (Variation ID: 37902). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000213169	SCV000279255	pathogenic	not provided	2023-07-26	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 BRCA2-related cancers (Pietschmann et al., 2005; Konstantopoulou et al., 2014; Eccles et al., 2016; Ashour et al., 2019; Deng et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4643_4646del, 4643_4646delAGAA, 4643del4, or 4643delAGAA; This variant is associated with the following publications: (PMID: 26681682, 29922827, 34687993, 29752822, 30720243, 30972954, 31372034, 15918047, 24010542, 19877752, 19139771, 24312913, 15131399, 26295337, 28195393, 26109977, 26300996, 31825140, 33087929, 20104584, 33632156)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213169	SCV000296683	pathogenic	not provided	2015-04-20	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031483	SCV000327030	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031483	SCV000489707	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-11-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771386	SCV000903714	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-02	criteria provided, single submitter	clinical testing	This variant deletes 4 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. 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: 15918047, 24010542, 24312913, 26681682, 27153395) or colorectal cancer (PMID: 28195393). This variant has been identified in 1/248584 chromosomes 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	RCV000044410	SCV000918980	pathogenic	Hereditary breast ovarian cancer syndrome	2018-04-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4415_4418delAGAA (p.Lys1472ThrfsX6) 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. The variant allele was found at a frequency of 4.1e-06 in 243794 control chromosomes (gnomAD and publications). c.4415_4418delAGAA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lubinski 2004, Pietschmann 2005, Konstantopoulou 2014, Eccles 2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000771386	SCV001184189	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	The c.4415_4418delAGAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4415 to 4418, causing a translational frameshift with a predicted alternate stop codon (p.K1472Tfs*6). This pathogenic mutation, also designated as 4643del4, is located in the ovarian cancer cluster region (OCCR) and has been reported in multiple families with HBOC related cancers (Lubinski J et al. Fam Cancer. 2004;3(1):1-10; Pietschmann A et al. J. Cancer Res. Clin. Oncol.2005 Aug;131(8):552-8; Karami F and Mehdipour P. Biomed Res Int. 2013;2013:928562). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262273	SCV001440083	pathogenic	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000213169	SCV001447919	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Molecular Endocrinology Laboratory, Christian Medical College	RCV000031483	SCV002004007	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798043	SCV002043059	pathogenic	Breast and/or ovarian cancer	2020-03-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001262273	SCV004210366	pathogenic	Familial cancer of breast	2023-03-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044410	SCV004848255	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Lys1472ThrfsX6 variant in BRCA2 has been reported in at least 5 individuals with BRCA2-related cancers (Hansen 2017, Li 2018, Pietschmann 2005, Konstantopoulou 2014). It has also been identified in 1/112594 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1472 and leads to a premature termination codon 6 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: 37902). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
Institute of Human Genetics, University of Leipzig Medical Center	RCV004760348	SCV005368409	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-08-16	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR,PM2_SUP
Sharing Clinical Reports Project (SCRP)	RCV000031483	SCV000054088	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044410	SCV000587712	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000213169	SCV001552479	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Lys1472Thrfs*6 variant was identified in 6 of 2414 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome, breast, or ovarian cancer (Hansen 2017, Karami 2013, Konstantopoulou 2014, Lubinski 2004, Pietschmann 2005). The variant was also identified in dbSNP (ID: rs397507333) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx and six other submitters), LOVD 3.0 (7x as pathogenic), and in ARUP Laboratories (as definitely pathogenic) databases. The variant was not identified in COGR, Cosmic, UMD-LSDB, BIC Database, or Zhejiang University databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.4415_4418del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1472 and leads to a premature stop codon at position 1477. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in BRCA2 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
BRCAlab, Lund University	RCV000031483	SCV002588876	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162270	SCV002758424	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research