rs17782839
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001040108.2(MLH3):c.2896T>C(p.Ser966Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,614,142 control chromosomes in the GnomAD database, including 341 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S966L) has been classified as Uncertain significance.
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.2896T>C | p.Ser966Pro | missense_variant | 2/13 | ENST00000355774.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH3 | ENST00000355774.7 | c.2896T>C | p.Ser966Pro | missense_variant | 2/13 | 5 | NM_001040108.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0115 AC: 1754AN: 152220Hom.: 31 Cov.: 32
GnomAD3 exomes AF: 0.0156 AC: 3912AN: 251224Hom.: 55 AF XY: 0.0178 AC XY: 2419AN XY: 135778
GnomAD4 exome AF: 0.0167 AC: 24355AN: 1461804Hom.: 310 Cov.: 34 AF XY: 0.0178 AC XY: 12916AN XY: 727206
GnomAD4 genome ? AF: 0.0115 AC: 1751AN: 152338Hom.: 31 Cov.: 32 AF XY: 0.0114 AC XY: 851AN XY: 74490
ClinVar
Submissions by phenotype
not specified Benign:4
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 | - | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
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 12, 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:2
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MLH3 p.Ser966Pro variant was identified in the literature, however the frequency of this variant in an affected population was not provided. In a study by Talseth-Palmer et al., targeted NGS showed variant c.2896T>C to be a benign variation (Talseth-Palmer_2016_PMID: 26811195). The variant was identified in dbSNP (ID: rs17782839) as “With Likely benign allele”. In ClinVar, there were two submissions: benign by Invitae and likely benign by Illumina Clinical Services Laboratory with the associated conditions of Lynch syndrome and MLH3-Related Lynch Syndrome. The variant was also found in Clinvitae and LOVD 3.0 databases. The variant was not identified in Cosmic, MutDB, and UMD-LSDB databases. The variant was identified in control databases in 4160 of 282636 chromosomes (59 homozygous) at a frequency of 0.014719 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: South Asian in 1271 of 30610 chromosomes (freq: 0.04152), Ashkenazi Jewish in 238 of 10366 chromosomes (freq: 2296), European (non-Finnish) in 2128 of 128974 chromosomes (freq: 0.0165), Other in 110 of 7218 chromosomes (freq: 0.01524), Latino in 241 of 35430 chromosomes (freq: 0.006802), European (Finnish) in 126 of 25122 chromosomes (freq: 0.005016), African in 43 of 24962 chromosomes (freq: 0.001723), and East Asian in 3 of 19954 chromosomes (freq: 0.00015). 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.Ser966Pro residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, 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 08, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at