NM_000249.4(MLH1):c.164G>A (p.Gly55Asp) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 24, 2020
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:: RCV000534909.6

Allele description [Variation Report for NM_000249.4(MLH1):c.164G>A (p.Gly55Asp)]

NM_000249.4(MLH1):c.164G>A (p.Gly55Asp)

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.164G>A (p.Gly55Asp)

HGVS:

NC_000003.12:g.36996666G>A
NG_007109.2:g.8317G>A
NG_008418.1:g.1639C>T
NM_000249.4:c.164G>AMANE SELECT
NM_001167617.3:c.-126G>A
NM_001167618.3:c.-560G>A
NM_001167619.3:c.-468G>A
NM_001258271.2:c.164G>A
NM_001258273.2:c.-517+3003G>A
NM_001258274.3:c.-705G>A
NM_001354615.2:c.-463G>A
NM_001354616.2:c.-468G>A
NM_001354617.2:c.-560G>A
NM_001354618.2:c.-560G>A
NM_001354619.2:c.-560G>A
NM_001354620.2:c.-126G>A
NM_001354621.2:c.-653G>A
NM_001354622.2:c.-766G>A
NM_001354623.2:c.-723+2776G>A
NM_001354624.2:c.-663G>A
NM_001354625.2:c.-566G>A
NM_001354626.2:c.-663G>A
NM_001354627.2:c.-663G>A
NM_001354628.2:c.164G>A
NM_001354629.2:c.164G>A
NM_001354630.2:c.164G>A
NP_000240.1:p.Gly55Asp
NP_000240.1:p.Gly55Asp
NP_001245200.1:p.Gly55Asp
NP_001341557.1:p.Gly55Asp
NP_001341558.1:p.Gly55Asp
NP_001341559.1:p.Gly55Asp
LRG_216t1:c.164G>A
LRG_216:g.8317G>A
LRG_216p1:p.Gly55Asp
NC_000003.11:g.37038157G>A
NM_000249.3:c.164G>A

Protein change:

G55D

Links:

dbSNP: rs1553638787

NCBI 1000 Genomes Browser:

rs1553638787

Molecular consequence:

NM_001167617.3:c.-126G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-560G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-468G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-705G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-463G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-468G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-560G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-560G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-560G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-126G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-653G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-766G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-663G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-566G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-663G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-663G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3003G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2776G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.164G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.164G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.164G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.164G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.164G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000625087	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 24, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15475387, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000625087

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 24, 2020)

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

Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain.

Ellison AR, Lofing J, Bitter GA.

Nucleic Acids Res. 2004 Oct 8;32(18):5321-38. Print 2004.

PubMed [citation]

PMID:: 15475387
PMCID:: PMC524276

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000625087.5

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

Description

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change moderately impairs mismatch repair function in a yeast assay (PMID: 15475387). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an MLH1-related disease. This sequence change replaces glycine with aspartic acid at codon 55 of the MLH1 protein (p.Gly55Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid.

#	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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