3-37020402-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBS1BS2

The NM_000249.4(MLH1):​c.977T>C​(p.Val326Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000579 in 1,614,136 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00043 ( 2 hom., cov: 33)
Exomes 𝑓: 0.00059 ( 2 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

7
10
2

Clinical Significance

Benign reviewed by expert panel U:2B:27O:1

Conservation

PhyloP100: 7.64
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.41998726).
BP6
Variant 3-37020402-T-C is Benign according to our data. Variant chr3-37020402-T-C is described in ClinVar as [Benign]. Clinvar id is 42496.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37020402-T-C is described in Lovd as [Likely_benign]. Variant chr3-37020402-T-C is described in Lovd as [Benign]. Variant chr3-37020402-T-C is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000433 (66/152256) while in subpopulation SAS AF= 0.00166 (8/4824). AF 95% confidence interval is 0.000825. There are 2 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MLH1NM_000249.4 linkc.977T>C p.Val326Ala missense_variant Exon 11 of 19 ENST00000231790.8 NP_000240.1 P40692-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MLH1ENST00000231790.8 linkc.977T>C p.Val326Ala missense_variant Exon 11 of 19 1 NM_000249.4 ENSP00000231790.3 P40692-1

Frequencies

GnomAD3 genomes
AF:
0.000440
AC:
67
AN:
152138
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00166
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.000706
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000469
AC:
118
AN:
251388
Hom.:
1
AF XY:
0.000611
AC XY:
83
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000260
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00111
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000607
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000594
AC:
868
AN:
1461880
Hom.:
2
Cov.:
31
AF XY:
0.000671
AC XY:
488
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000268
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00140
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000606
Gnomad4 OTH exome
AF:
0.000596
GnomAD4 genome
AF:
0.000433
AC:
66
AN:
152256
Hom.:
2
Cov.:
33
AF XY:
0.000336
AC XY:
25
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00166
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000691
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000511
Hom.:
0
Bravo
AF:
0.000400
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00116
AC:
10
ExAC
AF:
0.000527
AC:
64
EpiCase
AF:
0.00109
EpiControl
AF:
0.000711

ClinVar

Significance: Benign
Submissions summary: Uncertain:2Benign:27Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:8Other:1
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 27, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

-
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 05, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The variant, MLH1 c.977T>C (p.Val326Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 278288 control chromosomes, predominantly at a frequency of 0.0011 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. This variant was found in two affected members from a Lynch family (example, Hardt 2011). Detailed genotypic and phenotypic information was not available to assert whether or not the variant co-segregated with disease. In contrast, in one family, this variant did not co-segregate with the disease: while one affected member was positive for the variant, other two affected members did not carry the variant (Pastrello 2011). In addition, tumor tissues from patients with this variant showed no loss of heterozygosity, normal expression of MLH1 or MSH2, and normal microsatellite instability (Dieumegard 2000, Spaepen 2006, Pastrello 2011, Hardt 2011). In vitro MMR and dominant mutator effect studies showed conflicting results (Shimodaira 1998, Trojan 2002, Takahashi 2007) although supporting a functional MMR activity (Trojan_2002). Furthermore, a yeast two-hybrid assay showed that hMLH1 V326A can interact with hPMS2 and hEXO1 (Kondo 2003) and the variant was shown to not affect normal splicing (Borras 2012). Twelve clinical diagnostic laboratories and one expert panel (INSIGHT) have submitted clinical-significance assessments for this variant to ClinVar without evidence for independent evaluation. Eleven of them, to include the expert panel have classified the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

Aug 13, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:6
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MLH1: BS1 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Apr 09, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 8574961, 22949387, 9697702, 20176959, 18561205, 10573010, 16736289, 8592341, 16885385, 10446963, 9506527, 10448273, 17594722, 24728327, 23588873, 25637381, 22736432, 24055113, 25871441, 10732761, 21239990, 12810663, 17510385, 21404117, 11781295, 11555625, 17192056, 22290698, 15340264, 10601588, 26976419, 24362816, 20533529, 30998989) -

Feb 13, 2017
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 11, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:5
Sep 28, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: 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. -

Oct 21, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Apr 03, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 27, 2018
True Health Diagnostics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 20, 2022
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome Uncertain:1Benign:2
Dec 21, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

Sep 05, 2013
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: research

Multifactorial likelihood analysis posterior probability <0.001 -

Sep 23, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Benign:2
May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Colorectal cancer, non-polyposis Uncertain:1
Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Breast and/or ovarian cancer Benign:1
Mar 03, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:1
Jul 24, 2014
Pathway Genomics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Muir-Torré syndrome Benign:1
Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.58
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Pathogenic
0.40
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
D;.;.;.;.;.;.
Eigen
Uncertain
0.68
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D;D;.;.;.;D;D
M_CAP
Uncertain
0.092
D
MetaRNN
Benign
0.42
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.59
D
MutationAssessor
Pathogenic
3.4
M;.;.;.;.;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.9
D;D;D;D;D;D;D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0020
D;D;D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D
Polyphen
0.62
P;.;.;.;.;.;.
Vest4
0.78
MVP
0.98
MPC
0.17
ClinPred
0.15
T
GERP RS
5.8
Varity_R
0.71
gMVP
0.58

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: rs63751049; hg19: chr3-37061893; API