ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1136A>C (p.Tyr379Ser) (rs143009528)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166929 SCV000217748 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing <p style="text-align:justify">The p.Y379S variant (also known as c.1136A>C), located in coding exon 12 of the MLH1 gene, results from an A to C substitution at nucleotide position 1136. The tyrosine at codon 379 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000481402 SCV000572658 uncertain significance not provided 2017-01-09 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1136A>C at the cDNA level, p.Tyr379Ser (Y379S) at the protein level, and results in the change of a Tyrosine to a Serine (TAT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Tyr379Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tyrosine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Tyr379Ser occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Tyr379Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000166929 SCV000904057 likely benign Hereditary cancer-predisposing syndrome 2017-01-13 criteria provided, single submitter clinical testing
Invitae RCV000805743 SCV000945711 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-04 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with serine at codon 379 of the MLH1 protein (p.Tyr379Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. This variant is present in population databases (rs143009528, ExAC 0.03%). This variant has been observed in a family affected with Gardner syndrome (PMID: 29845239). ClinVar contains an entry for this variant (Variation ID: 187221). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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