ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.226G>A (p.Val76Ile) (rs878853788)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233829 SCV000284056 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 76 of the MLH1 protein (p.Val76Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 237335). 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 disruptive, 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 RCV000485354 SCV000568901 uncertain significance not provided 2018-10-12 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.226G>A at the cDNA level, p.Val76Ile (V76I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). This variant has been reported in at least one individual with breast cancer (Tung 2016). MLH1 Val76Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). MLH1 Val76Ile is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Val76Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568460 SCV000662028 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000765730 SCV000897098 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000568460 SCV000911374 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-20 criteria provided, single submitter clinical testing

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