Submissions for variant NM_000059.4(BRCA2):c.631+4A>G

dbSNP: rs397507841

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000258315	SCV000327387	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000258315	SCV000605721	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379699	SCV001577546	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-22	criteria provided, single submitter	clinical testing	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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20455026, 31143303). ClinVar contains an entry for this variant (Variation ID: 52056). This variant has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer (PMID: 29339979, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 7 of the BRCA2 gene. It does not directly 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223776	SCV002502514	likely pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362664	SCV002656761	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-28	criteria provided, single submitter	clinical testing	The c.631+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 6 in the BRCA2 gene. This alteration was seen in a patient diagnosed with breast and ovarian cancer in her 50s. This patient also carried BRCA1 p.R1699Q, which is thought to be a moderate risk mutation. Family history was significant for breast cancer in the patient's sister and father, who were diagnosed at ages 43 and 76, respectively. Somatic testing indicated that the father carried both alterations. In addition, RT-PCR demonstrated skipping of coding exon 6 (Steffensen AY et al. Fam. Cancer. 2010 Sep;9(3):283-7; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14). This nucleotide position is well conserved in available vertebrate species. However, this alteration may be partially rescued by alternative splicing as it demonstrated only 50% loss of homology directed DNA repair activity (Mesman RLS et al. Genet Med, 2020 Aug;22:1355-1365). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.