rs28756982
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001040108.2(MLH3):c.1258G>A(p.Val420Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,609,024 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_001040108.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH3 | NM_001040108.2 | c.1258G>A | p.Val420Ile | missense_variant | 2/13 | ENST00000355774.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH3 | ENST00000355774.7 | c.1258G>A | p.Val420Ile | missense_variant | 2/13 | 5 | NM_001040108.2 | P1 | |
MLH3 | ENST00000380968.6 | c.1258G>A | p.Val420Ile | missense_variant | 2/12 | 1 | |||
MLH3 | ENST00000556257.5 | c.1258G>A | p.Val420Ile | missense_variant | 2/7 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0109 AC: 1657AN: 152122Hom.: 13 Cov.: 33
GnomAD3 exomes AF: 0.0114 AC: 2811AN: 246462Hom.: 31 AF XY: 0.0112 AC XY: 1496AN XY: 133112
GnomAD4 exome AF: 0.0140 AC: 20329AN: 1456784Hom.: 168 Cov.: 35 AF XY: 0.0136 AC XY: 9870AN XY: 724338
GnomAD4 genome ? AF: 0.0109 AC: 1656AN: 152240Hom.: 13 Cov.: 33 AF XY: 0.0111 AC XY: 825AN XY: 74430
ClinVar
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 30, 2020 | 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. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Colorectal cancer, hereditary nonpolyposis, type 7 Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 03, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
MLH3-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 19, 2019 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at