rs781637991

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000249.4(MLH1):​c.2024G>A​(p.Ser675Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S675I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MLH1
NM_000249.4 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.88
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 Uncertain_significance. Variant got 4 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000249.4
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MLH1NM_000249.4 linkuse as main transcriptc.2024G>A p.Ser675Asn missense_variant 18/19 ENST00000231790.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MLH1ENST00000231790.8 linkuse as main transcriptc.2024G>A p.Ser675Asn missense_variant 18/191 NM_000249.4 P1P40692-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251272
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135786
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsFeb 19, 2024- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 15, 2015This variant is denoted MLH1 c.2024G>A at the cDNA level and p.Ser675Asn (S675N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ser675Asn occurs at a position that is conserved in mammals and is located in a region that is required for interaction with PMS2, MLH3 and PMS1 (Pang 1997, Raevaara 2005). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Ser675Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeApr 28, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 234563). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (rs781637991, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 675 of the MLH1 protein (p.Ser675Asn). -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 09, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Uncertain
0.028
T
BayesDel_noAF
Uncertain
-0.030
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.74
D;.;.;.;.;.
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.76
T;T;.;.;.;T
M_CAP
Benign
0.066
D
MetaRNN
Uncertain
0.43
T;T;T;T;T;T
MetaSVM
Uncertain
0.38
D
MutationAssessor
Benign
1.8
L;.;.;.;.;.
MutationTaster
Benign
0.99
D;D;D;D;D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-1.6
N;N;N;N;N;N
REVEL
Uncertain
0.37
Sift
Benign
0.25
T;T;T;T;T;T
Sift4G
Benign
0.76
T;T;T;T;T;T
Polyphen
0.10
B;.;.;.;.;.
Vest4
0.56
MutPred
0.39
Loss of phosphorylation at S675 (P = 0.0594);.;.;.;.;.;
MVP
0.84
MPC
0.064
ClinPred
0.38
T
GERP RS
5.9
Varity_R
0.42
gMVP
0.66

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: rs781637991; hg19: chr3-37090429; API