Submissions for variant NM_000249.4(MLH1):c.206G>A (p.Arg69Lys)

dbSNP: rs63751661

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000580736	SCV000684794	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 69 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein exhibits normal expression levels and normal mismatch repair activity (PMID: 17510385, 31697235). To our knowledge, this variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has not been identified 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.
Invitae	RCV000692100	SCV000819908	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 69 of the MLH1 protein (p.Arg69Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MLH1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 489896). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 11555625, 17510385, 31697235). 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.
Ambry Genetics	RCV000580736	SCV002725203	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-18	criteria provided, single submitter	clinical testing	The p.R69K variant (also known as c.206G>A), located in coding exon 2 of the MLH1 gene, results from a G to A substitution at nucleotide position 206. The arginine at codon 69 is replaced by lysine, an amino acid with highly similar properties. This variant has demonstrated reduced mismatch repair activity in two separate studies (Ellison AR et al. Hum. Mol. Genet., 2001 Sep;10:1889-900; Takahashi M et al. Cancer Res., 2007 May;67:4595-604). This alteration was detected in a patient with colon cancer who had at least two family members with colorectal and/or endometrial cancer in two generations (Stojcev Z et al. Acta Biochim Pol, 2013 Jun;60:195-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004001251	SCV004835253	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 69 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein exhibits normal expression levels and normal mismatch repair activity (PMID: 17510385, 31697235). To our knowledge, this variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has not been identified 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.