NM_000249.4(MLH1):c.163G>A (p.Gly55Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 30, 2015
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:: RCV002402415.2

Allele description [Variation Report for NM_000249.4(MLH1):c.163G>A (p.Gly55Ser)]

NM_000249.4(MLH1):c.163G>A (p.Gly55Ser)

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.163G>A (p.Gly55Ser)

HGVS:

NC_000003.12:g.36996665G>A
NG_007109.2:g.8316G>A
NG_008418.1:g.1640C>T
NM_000249.4:c.163G>AMANE SELECT
NM_001167617.3:c.-127G>A
NM_001167618.3:c.-561G>A
NM_001167619.3:c.-469G>A
NM_001258271.2:c.163G>A
NM_001258273.2:c.-517+3002G>A
NM_001258274.3:c.-706G>A
NM_001354615.2:c.-464G>A
NM_001354616.2:c.-469G>A
NM_001354617.2:c.-561G>A
NM_001354618.2:c.-561G>A
NM_001354619.2:c.-561G>A
NM_001354620.2:c.-127G>A
NM_001354621.2:c.-654G>A
NM_001354622.2:c.-767G>A
NM_001354623.2:c.-723+2775G>A
NM_001354624.2:c.-664G>A
NM_001354625.2:c.-567G>A
NM_001354626.2:c.-664G>A
NM_001354627.2:c.-664G>A
NM_001354628.2:c.163G>A
NM_001354629.2:c.163G>A
NM_001354630.2:c.163G>A
NP_000240.1:p.Gly55Ser
NP_000240.1:p.Gly55Ser
NP_001245200.1:p.Gly55Ser
NP_001341557.1:p.Gly55Ser
NP_001341558.1:p.Gly55Ser
NP_001341559.1:p.Gly55Ser
LRG_216t1:c.163G>A
LRG_216:g.8316G>A
LRG_216p1:p.Gly55Ser
NC_000003.11:g.37038156G>A
NM_000249.3:c.163G>A

Protein change:

G55S

Links:

dbSNP: rs1064796005

NCBI 1000 Genomes Browser:

rs1064796005

Molecular consequence:

NM_001167617.3:c.-127G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-561G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-469G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-706G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-464G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-469G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-561G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-561G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-561G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-127G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-654G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-767G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-664G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-567G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-664G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-664G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3002G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2775G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.163G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.163G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.163G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.163G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.163G>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
SCV002704557	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 30, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002704557

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 30, 2015)

germline

clinical testing

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

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

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

Details of each submission

From Ambry Genetics, SCV002704557.2

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

Description

The p.G55S variant (also known as c.163G>A), located in coding exon 2 of the MLH1 gene, results from a G to A substitution at nucleotide position 163. The glycine at codon 55 is replaced by serine, an amino acid with similar properties. The effect of this alteration in a hybrid yeast-human MLH1 has been assessed and authors report 34-66% loss of MMR compared to wild type (Ellison AR et al, Nucleic Acids Res. 2004 ; 32(18):5321-38). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 115000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Since supporting evidence is limited at this time, the clinical significance of p.G55S 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: Sep 29, 2024

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