Submissions for variant NM_000249.4(MLH1):c.954C>A (p.His318Gln)

dbSNP: rs146777069

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167219	SCV000218056	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-13	criteria provided, single submitter	clinical testing	The p.H318Q variant (also known as c.954C>A), located in coding exon 11 of the MLH1 gene, results from a C to A substitution at nucleotide position 954. The histidine at codon 318 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available 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.
Invitae	RCV000702569	SCV000831428	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-06-01	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 318 of the MLH1 protein (p.His318Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 187486). 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.
Color Diagnostics, LLC DBA Color Health	RCV000167219	SCV001345270	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-22	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 318 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with unilateral breast cancer (PMID: 33558524). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV003468801	SCV004195067	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995574	SCV004840929	uncertain significance	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 318 of the MLH1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Center of Medical Genetics and Primary Health Care	RCV001005036	SCV000987293	uncertain significance	Familial cancer of breast	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: A functional DNA Mismatch Repair domain (I216-334L aa), which is an ATP binding site. Hot-spot has 36 non-VUS coding variants (22 pathogenic and 14 benign), pathogenicity = 61.1%, proximity score 11.279 > threshold 2.472. PM2 Pathogenic Moderate: Variant not found in GnomAD exomes. Variant not found in GnomAD genomes. PP2 Pathogenic Supporting: 198 out of 264 non-VUS missense variants in gene MLH1 are pathogenic = 75.0% > threshold of 51.0%, and 914 out of 2,356 clinically reported variants in gene MLH1 are pathogenic = 38.8% > threshold of 12.0%. BP4 Benign Supporting: 6 benign predictions from DANN, EIGEN, FATHMM-MKL, MVP, PrimateAI and REVEL vs 5 pathogenic predictions from DEOGEN2, M-CAP, MutationAssessor, MutationTaster and SIFT and the position is not conserved. Therefore, it has been classified as a variant of uncertain significance.