NM_000249.4(MLH1):c.122A>G (p.Asp41Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 11, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002362707.2

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]

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
SCV002666816	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 11, 2022)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 15300854, 15365996, 15475387, 15849733, 17192056, 18383312, 18561205, 20233461, 21404117, 22949387, 23403630, 25060679, 26247049, 27435373, 28874130, 29360550 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002666816

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 11, 2022)

germline

clinical testing

PubMed (16)
[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

RNA analysis reveals splicing mutations and loss of expression defects in MLH1 and BRCA1.

Sharp A, Pichert G, Lucassen A, Eccles D.

Hum Mutat. 2004 Sep;24(3):272.

PubMed [citation]

PMID:: 15300854

Ten novel MSH2 and MLH1 germline mutations in families with HNPCC.

Krüger S, Bier A, Plaschke J, Höhl R, Aust DE, Kreuz FR, Pistorius SR, Saeger HD, Rothhammer V, Al-Taie O, Schackert HK.

Hum Mutat. 2004 Oct;24(4):351-2.

PubMed [citation]

PMID:: 15365996

See all PubMed Citations (16)

Details of each submission

From Ambry Genetics, SCV002666816.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

The p.D41G variant (also known as c.122A>G), located in coding exon 2 of the MLH1 gene, results from an A to G substitution at nucleotide position 122. The aspartic acid at codon 41 is replaced by glycine, an amino acid with similar properties. This variant has been detected in multiple patients who meet Amsterdam criteria and/or have colon cancer (Krüger S et al. Hum. Mutat., 2004 Oct;24:351-2; Wardell CP et al. J. Hepatol., 2018 05;68:959-969; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; van der Klift HM et al. Hum. Mutat., 2016 11;37:1162-1179; Pigatto F et al. Hered Cancer Clin Pract, 2004 Nov;2:175-84; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Sharp A et al. Hum. Mutat., 2004 Sep;24:272; Hardt K et al. Fam. Cancer, 2011 Jun;10:273-84). This variant demonstrated reduced expression and deficient mismatch repair (MMR) activity in an in vitro complementation assay (Hinrichsen I et al. Clin. Cancer Res., 2013 May;19:2432-41). In a yeast-based functional assay, this variant demonstrated partial loss of MMR activity (Ellison AR et al. Nucleic Acids Res., 2004 Oct;32:5321-38). RNA studies for this variant based on minigene assay and patient RNA analysis demonstrated out-of-frame exon 2 skipping, but this could not be confirmed in subsequent studies (Sharp A et al. Hum. Mutat., 2004 Sep;24:272; Tournier I et al. Hum. Mutat., 2008 Dec;29:1412-24; van der Klift HM et al. Mol Genet Genomic Med, 2015 Jul;3:327-45). 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

Last Updated: Sep 29, 2024

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