ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.283T>G (p.Ser95Ala) (rs63751070)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115478 SCV000149387 uncertain significance not provided 2018-05-15 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.283T>G at the cDNA level, p.Ser95Ala (S95A) at the protein level, and results in the change of a Serine to an Alanine (TCT>GCT). This variant is a non-conservative substitution in which a neutral polar amino acid is replaced with a neutral non-polar one, altering a position that is moderately conserved throughout evolution and is located in the MLH domain (Pang 1997). MLH1 Ser95Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furihata et al. (2001) identified MLH1 Ser95Ala in one sporadic, microsatellite stable urothelial transitional cell carcinoma tumor, and suggested neutrality based on lack of evolutionary conservation. This variant was also observed in combination with another missense variant, MLH1 Val716Met, in an individual with early-onset colorectal cancer and a family history of breast, stomach, and ovarian cancers (Hardt 2011). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain significance based on insufficient evidence for classification (Thompson 2014). In silico analyses are inconsistent with regard to the effect this mutation may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Ser95Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000215988 SCV000273862 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000409260 SCV000489231 uncertain significance Lynch syndrome II 2016-09-06 criteria provided, single submitter clinical testing
Invitae RCV000555517 SCV000625142 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces serine with alanine at codon 95 of the MLH1 protein (p.Ser95Ala). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and alanine. The frequency data for this variant (rs63751070) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported in an individual affected with colon cancer from a family meeting Bethesda criteria for Lynch syndrome (PMID: 21404117). ClinVar contains an entry for this variant (Variation ID: 90127) An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be tolerated (PMID: 22290698). However, this prediction has not been confirmed by published functional studies and its 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.
Color RCV000215988 SCV000911238 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-14 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030562 SCV001193606 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
True Health Diagnostics RCV000215988 SCV000788024 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-07 no assertion criteria provided clinical testing

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