NM_000249.4(MLH1):c.122A>G (p.Asp41Gly) AND Lynch syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 19, 2018
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000675183.2

Allele description [Variation Report for NM_000249.4(MLH1):c.122A>G (p.Asp41Gly)]

NM_000249.4(MLH1):c.122A>G (p.Asp41Gly)

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.122A>G (p.Asp41Gly)

HGVS:

NC_000003.12:g.36996624A>G
NG_007109.2:g.8275A>G
NG_008418.1:g.1681T>C
NM_000249.4:c.122A>GMANE SELECT
NM_001167617.3:c.-168A>G
NM_001167618.3:c.-602A>G
NM_001167619.3:c.-510A>G
NM_001258271.2:c.122A>G
NM_001258273.2:c.-517+2961A>G
NM_001258274.3:c.-747A>G
NM_001354615.2:c.-505A>G
NM_001354616.2:c.-510A>G
NM_001354617.2:c.-602A>G
NM_001354618.2:c.-602A>G
NM_001354619.2:c.-602A>G
NM_001354620.2:c.-168A>G
NM_001354621.2:c.-695A>G
NM_001354622.2:c.-808A>G
NM_001354623.2:c.-723+2734A>G
NM_001354624.2:c.-705A>G
NM_001354625.2:c.-608A>G
NM_001354626.2:c.-705A>G
NM_001354627.2:c.-705A>G
NM_001354628.2:c.122A>G
NM_001354629.2:c.122A>G
NM_001354630.2:c.122A>G
NP_000240.1:p.Asp41Gly
NP_000240.1:p.Asp41Gly
NP_001245200.1:p.Asp41Gly
NP_001341557.1:p.Asp41Gly
NP_001341558.1:p.Asp41Gly
NP_001341559.1:p.Asp41Gly
LRG_216t1:c.122A>G
LRG_216:g.8275A>G
LRG_216p1:p.Asp41Gly
NC_000003.11:g.37038115A>G
NM_000249.3:c.122A>G
P40692:p.Asp41Gly
p.(Asp41Gly)

Protein change:

D41G

Links:

UniProtKB: P40692#VAR_043390; dbSNP: rs63751094

NCBI 1000 Genomes Browser:

rs63751094

Molecular consequence:

NM_001167617.3:c.-168A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-602A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-510A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-747A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-505A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-510A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-602A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-602A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-602A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-168A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-695A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-808A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-705A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-608A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-705A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-705A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+2961A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2734A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.122A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.122A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.122A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.122A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.122A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Lynch syndrome
Identifiers:: MONDO: MONDO:0005835; MedGen: C4552100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000106148	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	reviewed by expert panel (Guidelines v2.4)	Pathogenic (Dec 19, 2018)	germline	curation	Citation Link,
SCV000800818	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 13, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000106148

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

reviewed by expert panel

(Guidelines v2.4)

Pathogenic
(Dec 19, 2018)

germline

curation

Citation Link,

SCV000800818

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 13, 2018)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

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 International Society for Gastrointestinal Hereditary Tumours (InSiGHT), SCV000106148.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

Multifactorial likelihood analysis posterior probability >0.99 (1.000)

#	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 Cancer Variant Interpretation Group UK, Institute of Cancer Research, London, SCV000800818.1

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

Description

Data used in classification: Single UK family with 11 informative meiosis (1:2048) (PP1_very_strong). Same amino acid residue as Asp41His (classified by INSIGHT as pathogenic) (PM5). The variant was observed in 3 independent UK families undergoing clinical diagnostic testing. There are additional reports of this variant on InSight (11 entries) and MLH1 LOVD (10 entries) (PS4_mod). The variant is absent GNOMAD NFE (63,369 individuals) and also in the remainder of the GNOMAD populations (75,263 individuals) (PM2_mod). 2/2 UK pedigrees for which we have tumour data demonstrated MSI in the tumour of the proband. Kruger S et al. Hum Mutat. 2004;24(4):351-2 report Amsterdam positive family (proband with colon cancer at 35 (ascending); [father: metachronous colon cancers: ascending colon (44), transverse colon (52) paternal grandmother: colon cancer (40)] ) with MSI-high but no loss of expression on IHC (PS3_mod). Same amino acid residue as Asp41His (classified by INSIGHT as pathogenic) (PM5). Predicted deleterious on AlignGVGD, SIFT, Polyphen2 HumVar (and also MAPP) (PP3). Additional Information (not included in classification): mRNA studies using sample from affected patient undertaken at molecular diagnostic laboratory demonstrated frame-shifting alteration in cDNA sequence: Minigene reported in Van der klift HM, et al. Mol Genet Genomic Med. 2015;3(4):327-45, reports mixed sequence products. Prior classification as Class 5 using multifactorial analysis (Insight paper 2012). Comment: Initially it was thought that this variant exerted pathogenicity through effect on splicing. However, in silico splicing predictions and splicing assay results are mixed. It may exert effect through missense impact on protein. Regardless of mechanisms, there are (i) multiple lines of generic functional evidence supporting this variant resulting in MMR deficiency and (ii) extremely strong genetic epidemiological evidence supporting pathogenicity (which is likewise agnostic to mechanism).

#	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		3	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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