3-37042330-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000249.4(MLH1):​c.1730C>T​(p.Ser577Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000194 in 1,598,554 control chromosomes in the GnomAD database, including 1 homozygotes. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S577S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 1 hom. )

Consequence

MLH1
NM_000249.4 missense, splice_region

Scores

7
10
2
Splicing: ADA: 0.9898
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:4O:1

Conservation

PhyloP100: 7.06
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 Likely_benign. Variant got -1 ACMG points.

BP6
Variant 3-37042330-C-T is Benign according to our data. Variant chr3-37042330-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127619.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=11, Benign=2, Likely_benign=2, not_provided=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MLH1NM_000249.4 linkc.1730C>T p.Ser577Leu missense_variant, splice_region_variant Exon 15 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.1730C>T p.Ser577Leu missense_variant, splice_region_variant Exon 15 of 19 1 NM_000249.4 ENSP00000231790.3 P40692-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152110
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251202
Hom.:
1
AF XY:
0.0000589
AC XY:
8
AN XY:
135766
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000707
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000187
AC:
27
AN:
1446444
Hom.:
1
Cov.:
29
AF XY:
0.0000180
AC XY:
13
AN XY:
720782
show subpopulations
Gnomad4 AFR exome
AF:
0.0000603
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000118
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152110
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000115
Hom.:
0
Bravo
AF:
0.0000945
ExAC
AF:
0.0000577
AC:
7
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:4Benign:1
Jun 23, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 27, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 25, 2024
Myriad Genetics, Inc.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -

May 22, 2024
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The MLH1 c.1730C>T (p.Ser577Leu) missense change has a maximum subpopulation frequency of 0.07% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with Lynch syndrome-associated tumors (PMID: 27601186; 28767289). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not provided Uncertain:2Benign:1
Feb 03, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Observed in individuals with a personal or family history of Lynch syndrome-associated cancers and in a healthy individual undergoing whole genome sequencing (Chao et al., 2008; Bodian et al., 2014; Lagerstedt-Robinson et al., 2016; Shindo et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as c.1007C>T; p.(Ser336Leu); This variant is associated with the following publications: (PMID: 33471991, 25186627), 30982232, 32914570, 31391288, 24728327, 27601186, 18383312, 28767289, 33281875, 32959997, 27535533, 12799449, 20533529, 22753075) -

Jan 13, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 01, 2020
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:2Other:1
Sep 06, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MLH1 c.1730C>T (p.Ser577Leu) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 251202 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database, including 1 homozygote.The variant, c.1730C>T, has been reported in the literature in individuals affected with colorectal cancer and other tumor phenotypes that belong to the Lynch Syndrome tumor spectrum (example: Chao_2008, Lagerstedt-Robinson_2016, Toh_2018, Li_2020, Jiang_2020, Shindo_2017 etc.). However, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. The variant has been also reported in the literature in multiple individuals affected with Breast Cancer (example: Tung_2015, Wang_2019 etc.). However, a recent large-scale Breast Cancer study reported the variant in 13/60466 BrC cases and 13/53461 controls, i.e. with a calculated odds ratio of 0.88, which suggests that this variant is not associated with a risk for Breast Cancer (Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar and classified the variant as VUS (n=8), likely benign (n=1) or benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

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

- -

May 06, 2015
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Sep 08, 2020
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: 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. -

Mar 20, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces serine with leucine at codon 577 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with Lynch syndrome, breast, and pancreatic cancer (PMID: 25186627, 27601186, 28767289, 31360874, 32659497, 32914570, 32959997, 33471991), as well as in multiple unaffected individuals reported in pancreatic cancer and breast cancer case-control studies (PMID: 32980694, 33471991). This variant has been identified in 17/282594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
May 23, 2017
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome Uncertain:1
Jul 10, 2024
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces serine with leucine at codon 577 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with Lynch syndrome, breast and pancreatic cancer (PMID: 25186627, 27601186, 28767289, 31360874, 32659497, 32914570, 32959997) and an unaffected individual in a pancreatic cancer case-control study (PMID: 32980694). However, this variant has not shown a significant association with breast cancer in a large case-control study, with an odds ratio reported at 0.884 (95% confidence interval: 0.41 to 1.907, PMID: 33471991). This variant has been identified in 17/282594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Feb 02, 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
Benign
0.27
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;.;.;.;.;.
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;.;.;.;D
M_CAP
Uncertain
0.21
D
MetaRNN
Uncertain
0.68
D;D;D;D;D;D
MetaSVM
Uncertain
0.47
D
MutationAssessor
Pathogenic
3.3
M;.;.;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-4.6
D;D;D;D;D;D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0080
D;D;D;D;D;D
Sift4G
Uncertain
0.017
D;D;D;D;D;D
Polyphen
0.30
B;.;.;.;.;.
Vest4
0.77
MVP
0.97
MPC
0.13
ClinPred
0.68
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.74
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.88
SpliceAI score (max)
0.23
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.23
Position offset: 1

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: rs56185292; hg19: chr3-37083821; COSMIC: COSV51621824; COSMIC: COSV51621824; API