NM_000249.4:c.644A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000249.4(MLH1):​c.644A>G​(p.Asn215Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N215T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.000018 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

1
15
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 8.86

Publications

8 publications found
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]
MLH1 Gene-Disease associations (from GenCC):
  • Lynch syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
  • Lynch syndrome 2
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
  • Muir-Torre syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
  • mismatch repair cancer syndrome 1
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
  • Lynch syndrome 1
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • ovarian cancer
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • malignant pancreatic neoplasm
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • rhabdomyosarcoma
    Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
  • prostate cancer
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • breast cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
  • hereditary breast carcinoma
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP6
Variant 3-37012066-A-G is Benign according to our data. Variant chr3-37012066-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90301.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MLH1NM_000249.4 linkc.644A>G p.Asn215Ser missense_variant Exon 8 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.644A>G p.Asn215Ser missense_variant Exon 8 of 19 1 NM_000249.4 ENSP00000231790.3 P40692-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000319
AC:
8
AN:
251154
AF XY:
0.0000368
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461728
Hom.:
0
Cov.:
30
AF XY:
0.0000220
AC XY:
16
AN XY:
727178
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.000301
AC:
26
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111878
Other (OTH)
AF:
0.00
AC:
0
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000426
Hom.:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Nov 19, 2021
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. -

Jan 26, 2023
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces asparagine with serine at codon 215 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). A functional study reported that this variant had a normal DNA damage response in an MLH1-null human cell line (PMID: 30998989). This variant has been reported in an individual from a Lynch syndrome family (PMID: 18561205) and in an individual affected with peritoneum cancer (PMID: 30093976). This variant has been identified in 8/251154 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. -

not specified Uncertain:1
Jul 06, 2017
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1
Jan 11, 2024
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Lynch syndrome Uncertain:1
Mar 07, 2023
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 asparagine with serine at codon 215 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study reported that this variant had a normal DNA damage response in an MLH1-null human cell line (PMID: 30998989). This variant has been reported in an individual from a Lynch syndrome family (PMID: 18561205 and the UMD database). This variant has been identified in 8/251154 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. -

not provided Uncertain:1
Feb 12, 2024
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a neutral effect: demonstrates cell survival comparable to other known neutral variants in a methylation tolerance assay (PMID: 30998989); This variant is associated with the following publications: (PMID: 30093976, 26333163, 18561205, 22753075, 30998989) -

Hereditary nonpolyposis colon cancer Benign:1
Apr 09, 2024
Mendelics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.064
T
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.69
D;.
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.73
D;D
MetaSVM
Uncertain
0.086
D
MutationAssessor
Uncertain
2.2
M;.
PhyloP100
8.9
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-2.8
D;D
REVEL
Uncertain
0.61
Sift
Uncertain
0.028
D;D
Sift4G
Uncertain
0.057
T;D
Polyphen
0.61
P;.
Vest4
0.73
MutPred
0.50
Gain of phosphorylation at N215 (P = 0.0889);.;
MVP
0.84
MPC
0.30
ClinPred
0.70
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.74
gMVP
0.72
Mutation Taster
=247/53
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
Splicevardb
1.0
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

Other links and lift over

dbSNP: rs267607775; hg19: chr3-37053557; API