ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.925C>T (p.Pro309Ser) (rs267607808)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000684787 SCV000259481 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 309 of the MLH1 protein (p.Pro309Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs267607808, ExAC 0.006%). This variant has been observed in an individual affected with colon cancer (PMID: 18033691). ClinVar contains an entry for this variant (Variation ID: 90444). 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 RCV000486267 SCV000567201 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.925C>T at the cDNA level, p.Pro309Ser (P309S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). This variant has been reported in at least one individual who was diagnosed with colorectal cancer, with studies on the tumor exhibiting microsatellite stability (MSS) and presence of MLH1, MSH2 and MSH6 on immunohistochemistry (IHC) (Barnetson 2008). MLH1 Pro309Ser was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Pro309Ser occurs at a position that is conserved across species and is not located in a known functional domain (Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Pro309Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574268 SCV000662018 likely benign Hereditary cancer-predisposing syndrome 2019-01-30 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
Color RCV000574268 SCV000689930 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-02 criteria provided, single submitter clinical testing

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