ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Variant summary: MLH1 c.290A>G (p.Tyr97Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 251380 control chromosomes, predominantly at a frequency of 0.0019 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.67 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.290A>G has been reported in the literature in individuals affected with colon cancer, breast cancer, low-grade glioma and liver hepatocellular carcinoma (Bartley_2012, Huang_2019, Dorling_2021, Lerner-Ellis_2021) but it has also been reported in unaffected controls (Dorling_2021). The individual affected with colon cancer was reported with high MSI, but positive MLH1, MSH2, MSH6, and PMS2 staining via IHC. This patient also did not meet the Amsterdam II criteria, nor did they have a family history of Lynch-syndrome associated cancers (Bartley_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22086678, 29625052, 33471991, 32885271). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 Multiple laboratories reported the variant with conflicting assessments: VUS (n=5), Benign (n=1) and likely Benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

Identified in an individual with colon cancer whose tumor showed microsatellite instability (MSI-H) but intact mismatch repair protein expression by immunohistochemistry (PMID: 22086678); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29625052, 33471991, 22753075, 16083711, 21120944, 32885271, 34326862, 38003901, 36451132, 22086678)

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.

The MLH1 p.Tyr97Cys variant was identified in 1 of 1182 proband chromosomes (frequency: 0.0008) from individuals or families with colon cancer (Bartley 2011). The variant was also identified in the following databases: dbSNP (ID: rs773647920) as "With Uncertain significance allele", ClinVar (3x uncertain significance, 1x likely benign), and Cosmic (1x, in carcinoma of the bone, Ewings sarcoma). The variant was not identified in MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 63 of 246178 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European in 1 of 111640 chromosomes (freq: 0.000009) and South Asian in 62 of 30782 chromosomes (freq: 0.002). The variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Tyr97 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. 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.