Submissions for variant NM_000059.4(BRCA2):c.4398_4402del (p.Leu1466fs)

dbSNP: rs80359444

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083104	SCV000282391	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044404	SCV000072417	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1466Phefs*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 present in population databases (rs755956766, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 17700570, 24504028, 24728189, 26681312, 27406733, 27831900). This variant is also known as 4625_4629delACATT and 1465_1467del. ClinVar contains an entry for this variant (Variation ID: 51640). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131078	SCV000186008	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-20	criteria provided, single submitter	clinical testing	The c.4398_4402delACATT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 4398 to 4402, causing a translational frameshift with a predicted alternate stop codon (p.L1466Ffs*2). This mutation (designated as 4625_4629delACATT) was reported in a Caucasian individual with prostate cancer diagnosed at age 51, who had a family history of prostate cancer in first-degree relatives, but no family history of breast or ovarian cancer (Agalliu I et al. Br. J. Cancer 2007 Sep;97(6):826-31). This mutation has also been reported in individuals with a personal history of breast, ovarian, and/or pancreatic cancer (Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Natarajan P et al. Sci. Transl. Med. 2016 Nov;8(364):364ra151; Walker EJ et al. Fam. Cancer. 2019 Apr;18:241-251). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000083104	SCV000195984	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000160288	SCV000210749	pathogenic	not provided	2023-09-15	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 a personal or family history consistent with pathogenic variants in this gene (Agalliu et al., 2007; Cunningham et al., 2014; Song et al., 2014; Natarajan et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4625_4629delACATT and 1465_1467del; This variant is associated with the following publications: (PMID: 22144684, 17700570, 24504028, 24728189, 26681312, 27831900, 26295337, 27406733, 30267352, 10923033, 30720243, 30322717, 32719484, 32918181, 30787465, 33507482)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083104	SCV000327023	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000083104	SCV000489178	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-08-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131078	SCV000683615	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-19	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 ovarian/breast cancer (PMID: 22711857, 24504028, 24728189, 26681312, 27406733) and prostate cancer (PMID: 17700570). This variant has been identified in 1/246640 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	RCV000044404	SCV000694767	pathogenic	Hereditary breast ovarian cancer syndrome	2019-07-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4398_4402delACATT (p.Leu1466PhefsX2) 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 allele was found at a frequency of 4e-06 in 249696 control chromosomes. c.4398_4402delACATT has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (Alsop_2012, Song_2014, George_2016, Susswein_2016, Rebbeck_2018) and prostate cancer (Agalliu_2007). One publication, George_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submissions including one expert panel, ENIGMA, (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160288	SCV000887815	pathogenic	not provided	2021-10-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044404	SCV001365791	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The p.Leu1466PhefsX2 variant in BRCA2 has been reported in at least 7 individuals with BRCA2-associated cancers (Agalliu 2007 PMID:17700570, Cunningham 2014 PMID:24504028, Susswein 2016 PMID:26681312, and Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has been identified in 0.003% (2/68012) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1). 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 1466 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 of function of the BRCA2 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 51640). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP criteria applied: PS4_Moderate, PM2_Supporting, PVS1.
Revvity Omics, Revvity	RCV000160288	SCV002021608	pathogenic	not provided	2021-06-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131078	SCV002533867	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	curation
Baylor Genetics	RCV003473340	SCV004211891	pathogenic	Familial cancer of breast	2024-01-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000160288	SCV004226543	pathogenic	not provided	2022-09-16	criteria provided, single submitter	clinical testing	PP5, PM2, PVS1
All of Us Research Program, National Institutes of Health	RCV004803178	SCV004845677	pathogenic	BRCA2-related cancer predisposition	2024-05-10	criteria provided, single submitter	clinical testing	The c.4398_4402del variant in the BRCA2 gene is located on the exon 11 and is predicted to shift the reading frame such that it introduces a premature translation termination codon (p.Leu1466Phefs*2), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 29446198, 29446198, 26681312). Other protein termination codon variants located in the same exon (p.Ser1404*, p.Gln2160*, p.Cys2256*) have been classified as pathogenic (ClinVar ID: 91815, 266950, 52180). Loss-of-function variants in the BRCA2 gene are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar and interpreted as pathogenic by the expert panel (ID: 51640). The variant is rare in general population according to gnomAD (1/246640 chromosomes). Therefore, the c.4398_4402del (p.Leu1466Phefs*2) variant in the BRCA2 gene has been classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005003441	SCV005633910	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-05-08	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083104	SCV000115178	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083104	SCV000146417	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353793	SCV000591902	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Leu1466PhefsX2 variant was not identified in the literature but was identified in dbSNP as a pathogenic allele (ID: rs80359444), in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 1 of 119188 chromosomes (frequency: 8.39E-06) (or 1 individual from a population of 32803 European (Non-Finnish) individuals and none from East Asian, African, Latino, South Asian, European (Finnish) or Other individuals. It was also identified in the Clinvitae database (4X), the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports, Invitae, BIC, Ambry Genetics and GeneDX), the BIC database (3X with pathogenic clinical importance), and UMD (4X as a causal variant). The p.Leu1466PhefsX2 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1466 and leads to a premature stop codon 2 codons downstream. 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 hereditary breast and ovarian cancer 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.