Submissions for variant NM_000179.2(MSH6):c.104C>T (p.Ala35Val) (rs776547943)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000461408	SCV000551111	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2018-08-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 35 of the MSH6 protein (p.Ala35Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs776547943, ExAC 0.002%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 410435). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000480657	SCV000567603	uncertain significance	not provided	2015-08-06	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.104C>T at the cDNA level, p.Ala35Val (A35V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala35Val 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. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ala35Val occurs at a position that is not conserved and is not located in a known functional domain (Kariola 2002). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH6 Ala35Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000573037	SCV000662364	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-24	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics	RCV000765675	SCV000897017	uncertain significance	Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5	2018-10-31	criteria provided, single submitter	clinical testing
Color	RCV000573037	SCV000908335	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-23	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV001192488	SCV001360644	uncertain significance	not specified	2019-11-26	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.104C>T (p.Ala35Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 235130 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.104C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.