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rs1800734

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000413740.2(MLH1):c.-93G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,283,016 control chromosomes in the GnomAD database, including 42,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.23 ( 4663 hom., cov: 33)
Exomes 𝑓: 0.25 ( 38212 hom. )

Consequence

MLH1
ENST00000413740.2 5_prime_UTR

Scores

2

Clinical Significance

Benign reviewed by expert panel U:1B:10

Conservation

PhyloP100: -0.737
Variant links:
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
Variant 3-36993455-G-A is Benign according to our data. Variant chr3-36993455-G-A is described in ClinVar as [Benign]. Clinvar id is 89600.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-36993455-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MLH1XM_047448155.1 linkuse as main transcript upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MLH1ENST00000413740.2 linkuse as main transcriptc.-93G>A 5_prime_UTR_variant 1/151
MLH1ENST00000536378.5 linkuse as main transcriptc.-725G>A 5_prime_UTR_variant 1/182 P40692-2
MLH1ENST00000673673.2 linkuse as main transcriptc.-93G>A 5_prime_UTR_variant 1/18

Frequencies

GnomAD3 genomes
AF:
0.232
AC:
35278
AN:
152130
Hom.:
4667
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.172
Gnomad AMI
AF:
0.170
Gnomad AMR
AF:
0.274
Gnomad ASJ
AF:
0.328
Gnomad EAS
AF:
0.554
Gnomad SAS
AF:
0.384
Gnomad FIN
AF:
0.247
Gnomad MID
AF:
0.367
Gnomad NFE
AF:
0.215
Gnomad OTH
AF:
0.260
GnomAD4 exome
AF:
0.246
AC:
278381
AN:
1130768
Hom.:
38212
Cov.:
16
AF XY:
0.251
AC XY:
144931
AN XY:
577786
show subpopulations
Gnomad4 AFR exome
AF:
0.168
Gnomad4 AMR exome
AF:
0.329
Gnomad4 ASJ exome
AF:
0.330
Gnomad4 EAS exome
AF:
0.545
Gnomad4 SAS exome
AF:
0.374
Gnomad4 FIN exome
AF:
0.253
Gnomad4 NFE exome
AF:
0.213
Gnomad4 OTH exome
AF:
0.266
GnomAD4 genome
AF:
0.232
AC:
35286
AN:
152248
Hom.:
4663
Cov.:
33
AF XY:
0.238
AC XY:
17732
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.172
Gnomad4 AMR
AF:
0.274
Gnomad4 ASJ
AF:
0.328
Gnomad4 EAS
AF:
0.554
Gnomad4 SAS
AF:
0.383
Gnomad4 FIN
AF:
0.247
Gnomad4 NFE
AF:
0.215
Gnomad4 OTH
AF:
0.262
Alfa
AF:
0.235
Hom.:
8641
Bravo
AF:
0.234
Asia WGS
AF:
0.445
AC:
1546
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:10
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, no assertion criteria providedliterature onlyOMIMFeb 15, 2007- -
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 02, 2022- -
Lynch syndrome Benign:1
Benign, reviewed by expert panelresearchInternational Society for Gastrointestinal Hereditary Tumours (InSiGHT)Sep 05, 2013MAF >1% -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 27895767, 31530880, 24325908, 25804231, 25421847, 30093976, 22878509, 28195176, 26275295, 15382050, 22371642, 23226285, 24205329, 21206982, 21348638, 24689082, 17374836, 19956916, 18712731, 18405947, 18523027, 23374646, 20060799, 21565826, 23621208, 20860725) -
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 19, 2024- -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 18, 2014This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.75
Cadd
Benign
3.6
Dann
Benign
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1800734; hg19: chr3-37034946; COSMIC: COSV99212309; COSMIC: COSV99212309; API