Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002384494 | SCV002693606 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-12-07 | criteria provided, single submitter | clinical testing | The c.131_132delCCinsTT variant, located in coding exon 2 of the MLH1 gene, results from an in-frame deletion of CC and insertion of TT at nucleotide positions 131 and 132. This results in the substitution of the serine residue for a phenylalanine residue at codon 44, an amino acid with highly dissimilar properties. This alteration was identified in an individual whose family history met Amsterdam II criteria for Lynch syndrome and colon tumor showed high microsatellite instability (MSI-H) with loss of both MLH1/PMS2 protein expression on immunohistochemistry (IHC) (Ambry internal data). In two different in vitro complementation assays using a MLH1 deficient colon cancer cell line, p.S44F demonstrated reduced relative mismatch repair activity (Takahashi M et al. Cancer Res., 2007 May;67:4595-604; Drost M et al. Hum. Mutat., 2010 Mar;31:247-53). Another alteration with the same amino acid change, but different nucleotide change, c.131C>T, has been reported in families that met Amsterdam criteria for Lynch syndrome with MSI-H tumors that displayed loss of MLH1 on IHC. This alteration segregated with disease in these families (Bronner CE, Nature 1994 Mar; 368(6468):258-61; Salahshor S et al. Lab. Invest., 2001 Apr;81:535-41; de Jong AE et al. Clin. Cancer Res., 2004 Feb;10:972-80; Lagerstedt Robinson K et al. J. Natl. Cancer Inst., 2007 Feb;99:291-9). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analysis (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV002548498 | SCV003220073 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-07-14 | criteria provided, single submitter | clinical testing | A different variant (c.131C>T) giving rise to the same protein effect has been determined to be pathogenic (PMID: 10037723, 12810663, 14871975, 15475387, 15731775). This suggests that this variant is also likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 10037723, 12810663, 15475387). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 1048910). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 44 of the MLH1 protein (p.Ser44Phe). |
| Department of Pathology and Laboratory Medicine, |
RCV001354327 | SCV001548917 | pathogenic | Endometrial carcinoma | no assertion criteria provided | clinical testing | The MLH1 p.Ser44Phe variant was not identified in the literature in an affected population nor was it identified in the dbSNP, ClinVar, UMD-LSDB, the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame insertion/deletion, which is predicted to result in the substitution of a serine (Ser) residue for phenylalanine (Phe) at codon 44. This variant was identified by our laboratory in a patient with an MLH1- and PMS2-deficient endometrial tumour. The same missense variant resulting from a different nucleotide change (c.131C>T) has been reported in ClinVar as pathogenic (evaluated by an InSiGHT expert panel in 2013). The variant was demonstrated to reduce binding between MLH1 and PMS2 in an interaction assay (Guerrette 1999). Yeast cells expressing the equivalent missense variant (p.Ser41Phe) had increased mutation frequencies caused by MMR defects (Ellison 2001). The p.Ser44 residue is moderately conserved across species and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. |