NM_000249.4(MLH1):c.199G>A (p.Gly67Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Feb 1, 2022
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:: RCV000128871.16

Allele description [Variation Report for NM_000249.4(MLH1):c.199G>A (p.Gly67Arg)]

NM_000249.4(MLH1):c.199G>A (p.Gly67Arg)

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.199G>A (p.Gly67Arg)

Other names:

p.G67R:GGG>AGG

HGVS:

NC_000003.12:g.36996701G>A
NG_007109.2:g.8352G>A
NG_008418.1:g.1604C>T
NM_000249.4:c.199G>AMANE SELECT
NM_001167617.3:c.-91G>A
NM_001167618.3:c.-525G>A
NM_001167619.3:c.-433G>A
NM_001258271.2:c.199G>A
NM_001258273.2:c.-517+3038G>A
NM_001258274.3:c.-670G>A
NM_001354615.2:c.-428G>A
NM_001354616.2:c.-433G>A
NM_001354617.2:c.-525G>A
NM_001354618.2:c.-525G>A
NM_001354619.2:c.-525G>A
NM_001354620.2:c.-91G>A
NM_001354621.2:c.-618G>A
NM_001354622.2:c.-731G>A
NM_001354623.2:c.-723+2811G>A
NM_001354624.2:c.-628G>A
NM_001354625.2:c.-531G>A
NM_001354626.2:c.-628G>A
NM_001354627.2:c.-628G>A
NM_001354628.2:c.199G>A
NM_001354629.2:c.199G>A
NM_001354630.2:c.199G>A
NP_000240.1:p.Gly67Arg
NP_000240.1:p.Gly67Arg
NP_001245200.1:p.Gly67Arg
NP_001341557.1:p.Gly67Arg
NP_001341558.1:p.Gly67Arg
NP_001341559.1:p.Gly67Arg
LRG_216t1:c.199G>A
LRG_216:g.8352G>A
LRG_216p1:p.Gly67Arg
NC_000003.11:g.37038192G>A
NM_000249.3:c.199G>A
P40692:p.Gly67Arg
p.G67R

Protein change:

G67R

Links:

UniProtKB: P40692#VAR_004439; dbSNP: rs63750206

NCBI 1000 Genomes Browser:

rs63750206

Molecular consequence:

NM_001167617.3:c.-91G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-525G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-433G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-670G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-428G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-433G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-525G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-525G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-525G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-91G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-618G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-731G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-628G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-531G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-628G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-628G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3038G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2811G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.199G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.199G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.199G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.199G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.199G>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
SCV000172728	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 29, 2021)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 10082584, 12070261, 12658575, 12810663, 16456782, 17510385, 19224586, 24362816, 26895986, 28874130, 29887214, 31494577, 32490589, 8521398, 9697702 Citation Link,
SCV000821734	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000911366	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 8521398, 12419761, 15563510, 15613555, 17312306, 18337503, 18383312, 21239990, 22949379, 24362816, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000172728

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 29, 2021)

germline

clinical testing

PubMed (15)
[See all records that cite these PMIDs]

Citation Link,

SCV000821734

GeneKor MSA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 1, 2020)

germline

clinical testing

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

SCV000911366

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 1, 2022)

germline

clinical testing

PubMed (11)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutator phenotypes conferred by MLH1 overexpression and by heterozygosity for mlh1 mutations.

Shcherbakova PV, Kunkel TA.

Mol Cell Biol. 1999 Apr;19(4):3177-83.

PubMed [citation]

PMID:: 10082584
PMCID:: PMC84111

Mismatch repair gene analysis in Catalonian families with colorectal cancer.

Palicio M, Balmaña J, González S, Blanco I, Marcuello E, Peinado MA, Julià G, Germà JR, López López JJ, Brunet J, Capellà G.

J Med Genet. 2002 Jun;39(6):E29. No abstract available.

PubMed [citation]

PMID:: 12070261
PMCID:: PMC1735159

See all PubMed Citations (24)

Details of each submission

From Ambry Genetics, SCV000172728.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

The p.G67R pathogenic mutation (also known as c.199G>A), located in coding exon 2 of the MLH1 gene, results from a G to A substitution at nucleotide position 199. The glycine at codon 67 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals and families affected with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several with tumors demonstrating loss of MLH1 by immunohistochemistry (IHC) (Tannergård P et al. Cancer Res. 1995 Dec;55(24):6092-6; Palicio M et al. J. Med. Genet. 2002 Jun;39(6):E29; Wagner A et al. Am. J. Hum. Genet. 2003 May;72(5):1088-100; Rosty C et al. BMJ Open. 2016 Feb;6:e010293; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Li F et al. Mol Genet Genomic Med, 2020 08;8:e1295; González-Acosta M et al. J Med Genet, 2020 04;57:269-273; Ambry internal data). In addition, functional studies have demonstrated that this variant results in low (5.9%) in vitro mismatch repair activity and decreased (<25%) relative MLH1 expression, and demonstrated no dominant mutator effect in reporter assays in yeast, which is consistent with pathogenicity (Takahashi M et al. Cancer Res. 2007 May;67(10):4595-604; Shimodaira H et al. Nat Genet, 1998 Aug;19:384-9; Shcherbakova PV et al. Mol Cell Biol 1999 Apr;19(4):3177-83). In a yeast two-hybrid assay, G67R displayed low levels of beta-galactosidase activity similar to known deleterious alterations (Kondo E et al. Cancer Res, 2003 Jun;63:3302-8). Using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as pathogenic (Shirts BH et al. Am J Hum Genet, 2018 07;103:19-29). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 GeneKor MSA, SCV000821734.2

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

Description

This variant is a point mutation that substitutes Glycine with Arginine in the position 67 of the MLH1 protein (p.Gly67Arg). This particular Glycine is highly conserved and in a functional domain, the "ATP-binding and hydrolysis domain" (PMID: 16083711 ). Additionally there is a large physicochemical difference between Glycine and Arginine. This finding has been described in international literature in patients with Lynch syndrome (PMID: 8521398, JPMID: 16810763). Furthermore, functional and in silico analysis (PMID: 17510385, PMID: 17510385) have indicated that this mutation is responsible of Lynch Syndrome occurrence in carriers. The mutation database ClinVar contains entries for this variant (Variation ID: 89992).

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

From Color Diagnostics, LLC DBA Color Health, SCV000911366.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This missense variant replaces glycine with arginine at codon 67 in the ATPase domain of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant reduction in protein expression and DNA mismatch repair activity (PMID: 24362816) and that mice transgenic for the mutant gene develop tumors and show a severely reduced survival rate (PMID: 18337503). This variant has been reported in individuals affected with Lynch syndrome (PMID: 8521398, 12419761, 15563510, 15613555, 17312306, 18383312, 21239990). Based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	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: Sep 29, 2024

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