ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1202G>A (p.Ser401Asn) (rs587779951)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222306 SCV000275412 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000222306 SCV000684728 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing
Counsyl RCV000663036 SCV000786074 uncertain significance Lynch syndrome II 2018-02-23 criteria provided, single submitter clinical testing
GeneDx RCV000115454 SCV000149363 uncertain significance not provided 2018-11-12 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1202G>A at the cDNA level, p.Ser401Asn (S401N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). This variant has been reported in at least one individual with colon cancer (Yurgelun 2017). MLH1 Ser401Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). MLH1 Ser401Asn is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether MLH1 Ser401Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000813295 SCV000953651 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 401 of the MLH1 protein (p.Ser401Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs587779951, ExAC 0.001%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 127611). 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 tolerated, 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.

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