Submissions for variant NM_000179.3(MSH6):c.1822A>G (p.Ile608Val)

gnomAD frequency: 0.00003  dbSNP: rs201613780

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589796	SCV000211282	uncertain significance	not provided	2023-05-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, melanoma, or a Lynch-syndrome related cancer and/or polyps, as well as in unaffected control groups (Yurgelun et al., 2015; Rosenthal et al., 2018; Yehia et al., 2018; Tsai et al., 2019; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 23621914, 30374176, 25980754, 30267214, 33471991, 17531815, 21120944, 29684080)
Invitae	RCV000196510	SCV000254283	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491442	SCV000580260	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-08	criteria provided, single submitter	clinical testing	The p.I608V variant (also known as c.1822A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1822. The isoleucine at codon 608 is replaced by valine, an amino acid with highly similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). In another study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). Additionally, in a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271428	SCV000695797	uncertain significance	not specified	2023-01-16	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1822A>G (p.Ile608Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of 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 2.4e-05 in 250564 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1822A>G has been reported in the literature with conflicting interpretations of pathogenicity ranging from VUS in settings of multigene panel testing for colorectal cancer (example, Yurgelun_2015) to a re-classification as Likely Benign based on patient-driven family studies using quantitative co-segregation likelihood ratios and a unified framework for Bayesian analysis with ACMG/AMP criteria (example, Tsai_2019). Additionally, the variant was identified in a healthy control case in a study assessing colorectal cancer or polyps cases (Rosenthal_2018) and was also identified in a case from The Cancer Genome Atlas database, however no additional information was provided (Yehia_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely Benign, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000757926	SCV000886444	likely benign	Lynch syndrome	2018-04-30	criteria provided, single submitter	research	The MSH6 variant designated as NM_000179.2:c.1822A>G (p.Ile608Val) is classified as likely benign. Based on in-silico scores the variant has a prior probability of pathogenicity of 10% (Thompson et al., 2013, PMID:22949379). Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303). Analysis of one family gave a likelihood ratio of 0.34 to 1 that this allele explains cancer in the family (Thompson, et al., 2003, PMID:2900794). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH6 function or modify cancer risk for Lynch syndrome. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Color Diagnostics, LLC DBA Color Health	RCV000491442	SCV000911114	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 608 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has also been identified in 8/281964 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000491442	SCV002535662	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000757926	SCV004840185	uncertain significance	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 608 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has also been identified in 8/281964 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000757926	SCV001550941	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Ile608Val variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome-related cancer and/or colorectal polyps (Yurgelun 2015). In this study, the variant co-occurred with a pathogenic MUTYH variant (c.734G>A, p.Arg245His) in the affected individual. The variant was also identified in dbSNP (ID: rs201613780) as “With Uncertain significance allele”, ClinVar (classified as likely benign by University of Washington Dept. of Laboratory Medicine and as uncertain significance by GeneDx, Invitae, Ambry Genetics, Color and Integrated Genetics/Laboratory Corp. of America). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 8 of 276892 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017); observed in the following populations: European Non-Finnish in 7 of 126468 chromosomes (freq: 0.00006) and European Finnish in 1 of 25790 chromosomes (freq: 0.00004), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian or South Asian populations. The p.Ile608 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Val variant impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.