Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001071771 | SCV001237092 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-07-02 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2 of the MLH1 protein (p.Ser2Ala). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 30521064). ClinVar contains an entry for this variant (Variation ID: 864552). 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. 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. |
| Ambry Genetics | RCV002348491 | SCV002645451 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-05 | criteria provided, single submitter | clinical testing | The p.S2A variant (also known as c.4T>G), located in coding exon 1 of the MLH1 gene, results from a T to G substitution at nucleotide position 4. The serine at codon 2 is replaced by alanine, an amino acid with similar properties. This alteration was identified in a 29 year old female diagnosed with colorectal cancer whose tumor showed loss of the MLH1 and PMS2 proteins on immunohistochemistry (IHC) (Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| All of Us Research Program, |
RCV004000206 | SCV004840127 | uncertain significance | Lynch syndrome | 2023-12-12 | criteria provided, single submitter | clinical testing | |
| Ding PR Lab, |
RCV001093665 | SCV001250846 | uncertain significance | Lynch syndrome 1 | no assertion criteria provided | clinical testing |