Submissions for variant NM_001040108.2(MLH3):c.1258G>A (p.Val420Ile)

gnomAD frequency: 0.01142  dbSNP: rs28756982

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000405727	SCV000285758	benign	Colorectal cancer, hereditary nonpolyposis, type 7	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000405727	SCV000388781	likely benign	Colorectal cancer, hereditary nonpolyposis, type 7	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001795360	SCV002551447	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001795360	SCV002680094	benign	not specified	2020-07-30	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000405727	SCV004015900	benign	Colorectal cancer, hereditary nonpolyposis, type 7	2023-07-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001354254	SCV004563911	benign	not provided	2023-11-03	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001354254	SCV005212601	likely benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354254	SCV001548820	likely benign	not provided		no assertion criteria provided	clinical testing	The MLH3 p.Val420Ile variant was identified in 4 of 174 proband chromosomes (frequency: 0.023) from individuals or families with Lynch Syndrome and was present in 2 of 180 control chromosomes (frequency: 0.01) from healthy individuals (Heinonen_2003_PMID: 12800209, Taylor_2006_PMID:16885347). The variant was also identified in dbSNP (ID: rs28756982) as likely benign, ClinVar (classified as benign by Invitae and likely benign by Illumina Clinical Service Laboratory), and LOVD 3.0 (classified as both uncertain significance and benign) databases. The variant was identified in control databases in 3222 of 277842 chromosomes (37 homozygous) at a frequency of 0.011597 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 847 of 25008 chromosomes (freq: 0.03387), European (non-Finnish) in 2026 of 127558 chromosomes (freq: 0.01588), Other in 87 of 7106 chromosomes (freq: 0.01224), Ashkenazi Jewish in 86 of 10164 chromosomes (freq: 0.008461), African in 64 of 24830 chromosomes (freq: 0.002578), Latino in 63 of 34392 chromosomes (freq: 0.001832), South Asian in 48 of 29030 chromosomes (freq: 0.001653), East Asian in 1 of 19754 chromosomes (freq: 0.000051). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Val420 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV001795360	SCV002034697	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001354254	SCV002035480	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003919926	SCV004731895	benign	MLH3-related disorder	2019-03-19	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).