NM_000249.4(MLH1):c.1117G>A (p.Gly373Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 5, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000166495.11

Allele description [Variation Report for NM_000249.4(MLH1):c.1117G>A (p.Gly373Arg)]

NM_000249.4(MLH1):c.1117G>A (p.Gly373Arg)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.1117G>A (p.Gly373Arg)

HGVS:

NC_000003.12:g.37025715G>A
NG_007109.2:g.37366G>A
NM_000249.4:c.1117G>AMANE SELECT
NM_001167617.3:c.823G>A
NM_001167618.3:c.394G>A
NM_001167619.3:c.394G>A
NM_001258271.2:c.1117G>A
NM_001258273.2:c.394G>A
NM_001258274.3:c.394G>A
NM_001354615.2:c.394G>A
NM_001354616.2:c.394G>A
NM_001354617.2:c.394G>A
NM_001354618.2:c.394G>A
NM_001354619.2:c.394G>A
NM_001354620.2:c.823G>A
NM_001354621.2:c.94G>A
NM_001354622.2:c.94G>A
NM_001354623.2:c.94G>A
NM_001354624.2:c.43G>A
NM_001354625.2:c.43G>A
NM_001354626.2:c.43G>A
NM_001354627.2:c.43G>A
NM_001354628.2:c.1117G>A
NM_001354629.2:c.1018G>A
NM_001354630.2:c.1117G>A
NP_000240.1:p.Gly373Arg
NP_000240.1:p.Gly373Arg
NP_001161089.1:p.Gly275Arg
NP_001161090.1:p.Gly132Arg
NP_001161091.1:p.Gly132Arg
NP_001245200.1:p.Gly373Arg
NP_001245202.1:p.Gly132Arg
NP_001245203.1:p.Gly132Arg
NP_001341544.1:p.Gly132Arg
NP_001341545.1:p.Gly132Arg
NP_001341546.1:p.Gly132Arg
NP_001341547.1:p.Gly132Arg
NP_001341548.1:p.Gly132Arg
NP_001341549.1:p.Gly275Arg
NP_001341550.1:p.Gly32Arg
NP_001341551.1:p.Gly32Arg
NP_001341552.1:p.Gly32Arg
NP_001341553.1:p.Gly15Arg
NP_001341554.1:p.Gly15Arg
NP_001341555.1:p.Gly15Arg
NP_001341556.1:p.Gly15Arg
NP_001341557.1:p.Gly373Arg
NP_001341558.1:p.Gly340Arg
NP_001341559.1:p.Gly373Arg
LRG_216t1:c.1117G>A
LRG_216:g.37366G>A
LRG_216p1:p.Gly373Arg
NC_000003.11:g.37067206G>A
NM_000249.3:c.1117G>A
p.G373R

Protein change:

G132R

Links:

dbSNP: rs766904735

NCBI 1000 Genomes Browser:

rs766904735

Molecular consequence:

NM_000249.4:c.1117G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.823G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1117G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.823G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.94G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.94G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.94G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.43G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.43G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.43G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.43G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1117G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1018G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1117G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000217294	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 5, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000904056	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26580448, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000217294

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 5, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000904056

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 1, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]

PMID:: 26580448
PMCID:: PMC4734119

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000217294.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000904056.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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