Submissions for variant NM_000059.4(BRCA2):c.9057A>G (p.Lys3019=)

dbSNP: rs1799956

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160164	SCV000210493	uncertain significance	not provided	2014-09-17	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.9057A>G at the DNA level. Although the variant is silent at the coding level, preserving a Lysine at codon 3019, it has been predicted by multiple splicing models to create a cryptic donor splice site leading to abnormal splicing. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 9057A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The nucleotide which is altered, a adenine (A) at base 9057, is highly conserved in mammals. Based on currently available information, it is unclear whether BRCA2 9057A>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000693870	SCV000822292	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-15	criteria provided, single submitter	clinical testing	This sequence change affects codon 3019 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with a personal and/or family history of prostate, breast and pancreatic cancer (Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 182258). Studies have shown that this variant results in activation of cryptic splice site and introduces a premature termination codon (external communication). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV001018727	SCV001179998	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-09	criteria provided, single submitter	clinical testing	The c.9057A>G pathogenic mutation (also known as p.K3019K), located in coding exon 22, results from an A to G substitution at nucleotide position 9057 of the BRCA2 gene. This nucleotide substitution does not change the amino acid at codon 3019. This nucleotide position is highly conserved through opossum. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is considered a disease-causing mutation.