Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075883 | SCV000106899 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Variant causes aberrant splicing leading to truncated protein: full inactivation of variant allele. |
| Invitae | RCV001854310 | SCV002273559 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-11-29 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with clinical features of Lynch syndrome (www.insight-database.org). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 281 of the MLH1 protein (p.Ala281Val). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. ClinVar contains an entry for this variant (Variation ID: 90390). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16995940, 18561205, 26761715; www.insight-database.org). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 17510385, 31697235). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function. |
| Ambry Genetics | RCV002444533 | SCV002678365 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-10-18 | criteria provided, single submitter | clinical testing | The c.842C>T variant (also known as p.A281V), located in coding exon 10 of the MLH1 gene, results from a C to T substitution at nucleotide position 842. The alanine at codon 281 is replaced by valine, an amino acid with similar properties. This alteration has been detected in multiple probands with a personal and/or family history of colorectal cancer (Stojcev Z et al. Acta Biochim Pol, 2013 Jun;60:195-8; Duzkale N et al. J Coll Physicians Surg Pak, 2021 Jul;30:811-816). This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated loss of PMS2 and diminished MLH1 expression by immunohistochemistry (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. However, RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Furthermore, this alteration demonstrated out-of-frame exon 10 skipping in minigene assays and utilizing RT-PCR on patient RNA (Lastella P et al. BMC Genomics, 2006 Sep;7:243; Soukarieh O et al. PLoS Genet., 2016 Jan;12:e1005756). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |