ClinVar Genomic variation as it relates to human health

No effect on splicing in minigene & RT-PCR assay

The variant is found in HEREDICANCER,COLO-HEREDIC panel(s).

Variant summary: MSH6 c.4001+12_4001+15delACTA variant results in 4 intronic nucleotides deletion, with 5/5 computational tools predicting no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0012 in 270798 control chromosomes (gnomAD). The observed variant frequency is approximately 8.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is benign. The variant, c.4001+12_4001+15delACTA, has been reported in the literature in individuals affected with Lynch Syndrome but also in unaffected controls and was classified as a polymorphism (Peterlongo_2003, Naruse_2009). In addition, the variant was detected in a patient with the pathogenic MSH2 variant c.211+1G>C that was shown to cause aberrant splicing (Naruse_2009). Since the penetrance of Lynch Syndrome (0.67) due to this variant appears to be lower than expected (0.8), no conclusions can be drawn from these data. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and the majority classified the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

MSH6: BS1

The MSH6 c.4001+12_4001+15dupACTA variant was identified in 1 of 1500 proband chromosomes (frequency: 0.0007) from individuals or families with CRC and was identified as a non-pathogenic variant (Woods 2010). The variant was also identified in dbSNP (ID: rs587782538) as “With other allele”, ClinVar (4x, as benign by GeneDx, as likely benign by Ambry, Invitae and Counsyl), Clinvitae (3x, as likely benign), and the Insight Colon Cancer Gene Variant Database (3x, as uncertain). The variant was not identified in COGR, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 75 of 270198 chromosomes at a frequency of 0.0003 in the following populations: African in 17 of 23654 chromosomes (freq. 0.0007), Latino in 13 of 34140 chromosomes (freq. 0.0004), European in 35 of 123578 chromosomes (freq. 0.0003), East Asian in 5 of 1860 chromosomes (freq. 0.0003), and other in 1 of 6346 chromosomes (freq. 0.0002), Ashkenazi Jewish in 1 of 10042 chromosomes (freq. 0.0001), South Asian in 3 of 30528 chromosomes (freq. 0.0001), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. A co-occurring pathogenic BRCA1 variant (c.709G>T, p.Glu237X) was identified in 1 individual with breast cancer in our laboratory, increasing the likelihood that c.4001+12_4001+15dupACTA variant does not have clinical significance In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.