Submissions for variant NM_000059.4(BRCA2):c.221del (p.Leu74fs)

dbSNP: rs1064793061

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000661650	SCV000783951	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-15	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneDx	RCV000482232	SCV000564758	pathogenic	not provided	2014-10-23	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA2 is denoted c.221delT at the cDNA level and p.Leu74ArgfsX6 (L74RfsX6) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAGC[T]GGCT. The deletion causes a frameshift, which changes a Leucine to an Arginine at codon 74, and creates a premature stop codon at position 6 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001225520	SCV001397803	pathogenic	Hereditary breast ovarian cancer syndrome	2019-11-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This sequence change creates a premature translational stop signal (p.Leu74Argfs*6) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 418075).