Submissions for variant NM_001040108.2(MLH3):c.2911G>A (p.Val971Ile)

gnomAD frequency: 0.00048  dbSNP: rs41555714

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001118345	SCV000551774	benign	Colorectal cancer, hereditary nonpolyposis, type 7	2024-01-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763945	SCV000894891	uncertain significance	Endometrial carcinoma; Colorectal cancer, hereditary nonpolyposis, type 7	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001118345	SCV001276618	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 7	2018-01-15	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV003321615	SCV002750970	likely benign	not specified	2020-07-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321615	SCV004027527	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356029	SCV001551083	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MLH3 p.Val971Ile variant was identified in a family with colorectal cancer; the variant was present in the female proband, her affected father as well as two unaffected relatives who may not yet have presented with disease. The proband's brother with tubular adenoma and another relative with ovarian cancer both did not carry the variant (Liu_2003_PMID:12702580). The variant was identified in dbSNP (ID: rs41555714), ClinVar (classified as uncertain significance by Invitae and Fulgent Genetics) and LOVD 3.0 (classified as a VUS, pathogenic and benign) but was not identified in Cosmic. The variant was identified in control databases in 178 of 282584 chromosomes (1 homozygous) at a frequency of 0.0006299 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 85 of 10362 chromosomes (freq: 0.008203), European (non-Finnish) in 72 of 128936 chromosomes (freq: 0.000558), Other in 4 of 7214 chromosomes (freq: 0.000555), Latino in 15 of 35430 chromosomes (freq: 0.000423) and European (Finnish) in 2 of 25120 chromosomes (freq: 0.00008), but was not observed in the African, East Asian, or South Asian populations. The p.Val971 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003925324	SCV004739179	benign	MLH3-related disorder	2020-01-16	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).