Submissions for variant NM_000059.4(BRCA2):c.4859T>G (p.Leu1620Ter)

dbSNP: rs80358710

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113353	SCV000300793	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113353	SCV000327098	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000657631	SCV000779374	pathogenic	not provided	2016-10-05	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4859T>G at the cDNA level and p.Leu1620Ter (L1620X) at the protein level. Using alternate nomenclature, this variant has been published as BRCA2 c.5087T>G. The substitution creates a nonsense variant, which changes a Leucine to a premature stop codon (TTA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in individuals with ovarian cancer and is considered pathogenic (Risch 2006, Zhang 2011).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496625	SCV001586069	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1620*) 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 (rs80358710, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 11179017). This variant is also known as T5087G. ClinVar contains an entry for this variant (Variation ID: 51730). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001525083	SCV001735098	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-04	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a 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 cancer (PMID: 21324516). This variant has been identified in 1/249834 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.
Ambry Genetics	RCV001525083	SCV002634888	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-18	criteria provided, single submitter	clinical testing	The p.L1620* pathogenic mutation (also known as c.4859T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 4859. This changes the amino acid from a leucine to a stop codon within coding exon 10. This alteration was identified in a Canadian individual diagnosed with ovarian cancer (Risch HA et al. Am J Hum Genet, 2001 Mar;68:700-10). 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 described in the literature as T5087G. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496625	SCV004847906	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Leu1620X variant in BRCA2 has been reported in at least 4 individuals with breast or ovarian cancer (Risch 2001, Zhang 2011, BIC database). It has also been identified in 1/113080 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 leads to a premature termination codon at position 1620, which is 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: 51730). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113353	SCV000146496	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496625	SCV000587728	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research