Submissions for variant NM_000059.4(BRCA2):c.1389_1390del (p.Val464fs)

dbSNP: rs80359283

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077255	SCV000282356	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	RCV000043794	SCV000071807	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val464Glyfs*3) 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 ovarian cancer (PMID: 10227398, 15024741, 16683254, 24549055, 26681312). This variant is also known as 1617delAG. ClinVar contains an entry for this variant (Variation ID: 51113). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000160277	SCV000210730	pathogenic	not provided	2018-06-14	criteria provided, single submitter	clinical testing	This deletion of 2 nucleotides in BRCA2 is denoted c.1389_1390delAG at the cDNA level and p.Val464GlyfsX3 (V464GfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAAC[delAG]TGGT. The deletion causes a frameshift, which changes a Valine to a Glycine at codon 464, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.1389_1390delAG, also published as BRCA2 1617_1618delAG or BRCA2 1617delAG using alternate nomenclature, has been reported in association with Hereditary Breast and Ovarian cancer (Goelen 1999, Claes 2004, Machackova 2008). We consider this variant to be pathogenic.
Ambry Genetics	RCV000214525	SCV000273209	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-28	criteria provided, single submitter	clinical testing	The c.1389_1390delAG pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of two nucleotides between nucleotide positions 1389 and 1390, causing a translational frameshift with a predicted alternate stop codon (p.V464Gfs*3). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation was reported in one Belgian family affected with both breast and ovarian cancer (Goelen G et al. J. Med. Genet. 1999 Apr;36(4):304-8), one Japanese male breast cancer patient (Momozawa Y et al. Nat Commun. 2018 10;9:4083), and in Czech families considered high-risk for breast and ovarian cancer (Foretova L et al. Hum. Mutat. 2004 Apr;23(4):397-8; Machackova E et al. BMC Cancer 2008 May;8:140). This alteration was identified in 1/10,030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18:823-32). 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 1617delAG, c.1617_1618delAG, and c.1389_1390del2 in published literature. 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	RCV000077255	SCV000326547	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214525	SCV000683420	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 10 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 at least 5 individuals affected with breast or ovarian cancer, including 2 male individuals (PMID: 21190077, 22711857, 24549055, 30287823, 34490083) and has been identified in 27 families among the CIMBA participants (PMID: 29446198). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 4/60466 cases and 2/53461 controls (OR=1.768 (95%CI 0.324 to 9.655); p-value=0.691) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001848). 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.
GeneKor MSA	RCV000585683	SCV000693557	pathogenic	Familial cancer of breast	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change deletes 2 nucleotide in exon 10 of the BRCA2 mRNA (c.1389_1390delAG), causing a frameshift after codon 464 and the creation of a premature translational stop signal 3 amino acid residues later (p.Val464Glyfs*3). This is expected to result in a truncated or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular truncation has been reported in the literature in families affected with breast and ovarian cancer (PMID: 10227398 ; Hum Mutat. 2004, 23:397-8; PMID: 16683254 ;PMID: 24549055). The mutation database ClinVar contains an entry for this variant (Variation ID: 51113).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160277	SCV000888977	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	The BRCA2 c.1389_1390del (p.Val464Glyfs*3) variant (also known as 1617delAG) 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, this variant has been reported in multiple individuals with breast/ovarian cancer (PMIDs: 34490083 (2021), 31159747 (2019), 31263054 (2019), 30287823 (2018), 30322717 (2018), 26681312 (2015), 18489799 (2008), 16683254 (2006), 10227398 (1999)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043794	SCV000916856	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1389_1390delAG (p.Val464GlyfsX3) 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 248414 control chromosomes (gnomAD). c.1389_1390delAG has been reported in the literature in multiple individuals affected with breast- and/or ovarian cancer (e.g. Goelen_1999, Foretova_2004, Claes_2004, Susswein_2015, Delgado_2011, Rebbeck_2018, Dorling_2021). 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. Eight other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	RCV000077255	SCV001519676	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
DASA	RCV001849297	SCV002107144	pathogenic	BRCA2-related disorder	2022-03-05	criteria provided, single submitter	clinical testing	The c.1389_1390del;p.(Val464Glyfs*3) is a null frameshift variant (NMD) in the BRCA2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 51113; PMID: 10227398; PMID: 24549055; PMID: 16683254; PMID: 15024741; PMID: 26681312; PMID: 29446198). PS4. This variant is not present in population databases (rs80359283- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.
Sema4, Sema4	RCV000214525	SCV002533230	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-09	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000160277	SCV003812430	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000585683	SCV004212834	pathogenic	Familial cancer of breast	2024-01-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077255	SCV004846914	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-26	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 10 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 at least 5 individuals affected with breast or ovarian cancer, including 2 male individuals (PMID: 21190077, 22711857, 24549055, 30287823, 34490083) and has been identified in 27 families among the CIMBA participants (PMID: 29446198). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 4/60466 cases and 2/53461 controls (OR=1.768 (95%CI 0.324 to 9.655); p-value=0.691) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001848). 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.
Sharing Clinical Reports Project (SCRP)	RCV000077255	SCV000109052	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077255	SCV000145863	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162364	SCV002758411	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research