Submissions for variant NM_000059.4(BRCA2):c.4470dup (p.Leu1491fs)

dbSNP: rs397507334

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031486	SCV000300750	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.
GeneDx	RCV000485961	SCV000564779	pathogenic	not provided	2017-09-06	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in BRCA2 is denoted c.4470dupA at the cDNA level and p.Leu1491ThrfsX23 (L1491TfsX23) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is AAAT[A]CTGA. The duplication causes a frameshift, which changes a Leucine to a Threonine at codon 1491, and creates a premature stop codon at position 23 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. we consider this variant to be pathogenic.
Ambry Genetics	RCV000562888	SCV000668833	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	The c.4470dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 4470, causing a translational frameshift with a predicted alternate stop codon (p.L1491Tfs*23). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637810	SCV000759289	pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1491Thrfs*23) 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 BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 37905). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485961	SCV000889047	pathogenic	not provided	2018-02-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000637810	SCV003801193	pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4470dupA (p.Leu1491ThrfsX23) 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 250468 control chromosomes. c.4470dupA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Kim_2017) as well as individuals affected with prostate cancer (e.g., Robinson_2017, Wu_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003473177	SCV004210491	likely pathogenic	Familial cancer of breast	2022-09-22	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031486	SCV000054091	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-06-11	no assertion criteria provided	clinical testing