NM_000249.4(MLH1):c.206G>A (p.Arg69Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 8, 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:: RCV000580736.14

Allele description [Variation Report for NM_000249.4(MLH1):c.206G>A (p.Arg69Lys)]

NM_000249.4(MLH1):c.206G>A (p.Arg69Lys)

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.206G>A (p.Arg69Lys)

HGVS:

NC_000003.12:g.36996708G>A
NG_007109.2:g.8359G>A
NG_008418.1:g.1597C>T
NM_000249.4:c.206G>AMANE SELECT
NM_001167617.3:c.-84G>A
NM_001167618.3:c.-518G>A
NM_001167619.3:c.-426G>A
NM_001258271.2:c.206G>A
NM_001258273.2:c.-517+3045G>A
NM_001258274.3:c.-663G>A
NM_001354615.2:c.-421G>A
NM_001354616.2:c.-426G>A
NM_001354617.2:c.-518G>A
NM_001354618.2:c.-518G>A
NM_001354619.2:c.-518G>A
NM_001354620.2:c.-84G>A
NM_001354621.2:c.-611G>A
NM_001354622.2:c.-724G>A
NM_001354623.2:c.-723+2818G>A
NM_001354624.2:c.-621G>A
NM_001354625.2:c.-524G>A
NM_001354626.2:c.-621G>A
NM_001354627.2:c.-621G>A
NM_001354628.2:c.206G>A
NM_001354629.2:c.206G>A
NM_001354630.2:c.206G>A
NP_000240.1:p.Arg69Lys
NP_000240.1:p.Arg69Lys
NP_001245200.1:p.Arg69Lys
NP_001341557.1:p.Arg69Lys
NP_001341558.1:p.Arg69Lys
NP_001341559.1:p.Arg69Lys
LRG_216t1:c.206G>A
LRG_216:g.8359G>A
LRG_216p1:p.Arg69Lys
NC_000003.11:g.37038199G>A
NM_000249.3:c.206G>A

Protein change:

R69K

Links:

dbSNP: rs63751661

NCBI 1000 Genomes Browser:

rs63751661

Molecular consequence:

NM_001167617.3:c.-84G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-518G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-426G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-663G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-421G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-426G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-518G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-518G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-518G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-84G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-611G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-724G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-621G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-524G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-621G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-621G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3045G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2818G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.206G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.206G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.206G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.206G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.206G>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
SCV000684794	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17510385, 31697235, 25741868
SCV002725203	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 18, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10627141, 11555625, 17510385, 23741719 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000684794

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 8, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002725203

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 18, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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

Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome.

Abildgaard AB, Stein A, Nielsen SV, Schultz-Knudsen K, Papaleo E, Shrikhande A, Hoffmann ER, Bernstein I, Gerdes AM, Takahashi M, Ishioka C, Lindorff-Larsen K, Hartmann-Petersen R.

Elife. 2019 Nov 7;8. doi:pii: e49138. 10.7554/eLife.49138.

PubMed [citation]

PMID:: 31697235
PMCID:: PMC6837844

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

See all PubMed Citations (6)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000684794.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces arginine with lysine at codon 69 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 the mutant protein exhibits normal expression levels and normal mismatch repair activity (PMID: 17510385, 31697235). To our knowledge, this variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has not been identified 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

From Ambry Genetics, SCV002725203.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.R69K variant (also known as c.206G>A), located in coding exon 2 of the MLH1 gene, results from a G to A substitution at nucleotide position 206. The arginine at codon 69 is replaced by lysine, an amino acid with highly similar properties. This variant has demonstrated reduced mismatch repair activity in two separate studies (Ellison AR et al. Hum. Mol. Genet., 2001 Sep;10:1889-900; Takahashi M et al. Cancer Res., 2007 May;67:4595-604). This alteration was detected in a patient with colon cancer who had at least two family members with colorectal and/or endometrial cancer in two generations (Stojcev Z et al. Acta Biochim Pol, 2013 Jun;60:195-8). This amino acid position is highly 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

Last Updated: Nov 10, 2024

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