rs786203264

Positions:

• chr3-37025715-G-A
• chr3-37025715-G-T
• chr3-37025715-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000249.4(MLH1):​c.1117G>A​(p.Gly373Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,702 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000012 (2 hom.)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:1
• Conservation: PhyloP100: 5.80

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33121333).
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1117G>A	p.Gly373Arg	missense_variant	12/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1117G>A	p.Gly373Arg	missense_variant	12/19	1	NM_000249.4	ENSP00000231790	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461702 Hom.: 2 Cov.: 34 AF XY: 0.0000124 AC XY: 9 AN XY: 727134

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000740 Hom.: 0

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 13, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	May 03, 2021	MLH1 NM_000249.3 exon 12 p.Gly373Arg (c.1117G>A): This variant has been reported in the literature in one individual with ALL (Zhang 2015 PMID:26580448). This variant is not present in large control databases but is present in ClinVar (Variation ID:186843). Evolutionary conservation and computational predictive tools for this variant are unclear. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Lynch syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This missense variant replaces glycine with arginine at codon 373 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 reported in an individual affected with leukemia (PMID: 26580448). This variant has been identified in 1/246196 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 01, 2022	This missense variant replaces glycine with arginine at codon 373 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 reported in an individual affected with leukemia (PMID: 26580448). This variant has been identified in 1/246196 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 05, 2023	The p.G373R variant (also known as c.1117G>A), located in coding exon 12 of the MLH1 gene, results from a G to A substitution at nucleotide position 1117. The glycine at codon 373 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole-genome sequencing and/or whole-exome sequencing; this patient was diagnosed with hypodiploid acute lymphocytic leukemia (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 19, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 373 of the MLH1 protein (p.Gly373Arg). This variant is present in population databases (rs766904735, gnomAD no frequency). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 186843). 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. In 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 03, 2020

Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26580448) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.;.;.;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;.;.;.;D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.087	T;T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T;T
Polyphen		0.066	B;.;.;.;.;.
Vest4		0.53
MutPred		0.34		Gain of solvent accessibility (P = 0.0037);.;.;.;.;.;
MVP		0.99
MPC		0.080
ClinPred		0.34	T
GERP RS		5.7
Varity_R		0.097
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs766904735; hg19: chr3-37067206;