NM_000249.4(MLH1):c.131C>G (p.Ser44Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 28, 2018
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:: RCV001010982.3

Allele description [Variation Report for NM_000249.4(MLH1):c.131C>G (p.Ser44Cys)]

NM_000249.4(MLH1):c.131C>G (p.Ser44Cys)

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.131C>G (p.Ser44Cys)

HGVS:

NC_000003.12:g.36996633C>G
NG_007109.2:g.8284C>G
NG_008418.1:g.1672G>C
NM_000249.4:c.131C>GMANE SELECT
NM_001167617.3:c.-159C>G
NM_001167618.3:c.-593C>G
NM_001167619.3:c.-501C>G
NM_001258271.2:c.131C>G
NM_001258273.2:c.-517+2970C>G
NM_001258274.3:c.-738C>G
NM_001354615.2:c.-496C>G
NM_001354616.2:c.-501C>G
NM_001354617.2:c.-593C>G
NM_001354618.2:c.-593C>G
NM_001354619.2:c.-593C>G
NM_001354620.2:c.-159C>G
NM_001354621.2:c.-686C>G
NM_001354622.2:c.-799C>G
NM_001354623.2:c.-723+2743C>G
NM_001354624.2:c.-696C>G
NM_001354625.2:c.-599C>G
NM_001354626.2:c.-696C>G
NM_001354627.2:c.-696C>G
NM_001354628.2:c.131C>G
NM_001354629.2:c.131C>G
NM_001354630.2:c.131C>G
NP_000240.1:p.Ser44Cys
NP_000240.1:p.Ser44Cys
NP_001245200.1:p.Ser44Cys
NP_001341557.1:p.Ser44Cys
NP_001341558.1:p.Ser44Cys
NP_001341559.1:p.Ser44Cys
LRG_216t1:c.131C>G
LRG_216:g.8284C>G
LRG_216p1:p.Ser44Cys
NC_000003.11:g.37038124C>G
NM_000249.3:c.131C>G

Protein change:

S44C

Links:

dbSNP: rs63751109

NCBI 1000 Genomes Browser:

rs63751109

Molecular consequence:

NM_001167617.3:c.-159C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-593C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-501C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-738C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-496C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-501C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-593C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-593C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-593C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-159C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-686C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-799C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-696C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-599C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-696C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-696C>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+2970C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2743C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.131C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.131C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.131C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.131C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.131C>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

Recent activity

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AP1 gamma subunit binding protein 1, isoform CRA_d [Homo sapiens]
AP1 gamma subunit binding protein 1, isoform CRA_d [Homo sapiens]
gi|119578002|gb|EAW57598.1||gnl|WGS |hCP1800804

Protein
Mus musculus presenilin associated, rhomboid-like (Parl), mRNA; nuclear gene for...
Mus musculus presenilin associated, rhomboid-like (Parl), mRNA; nuclear gene for mitochondrial product
gi|158508593|ref|NM_001005767.4|

Nucleotide
hypothetical protein [Pedobacter sp. B4-66]
hypothetical protein [Pedobacter sp. B4-66]
gi|2513913387|ref|WP_284445124.1|

Protein
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001171255	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 28, 2018)	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

SCV001171255

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 28, 2018)

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, SCV001171255.4

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

Description

The p.S44C variant (also known as c.131C>G), located in coding exon 2 of the MLH1 gene, results from a C to G substitution at nucleotide position 131. The serine at codon 44 is replaced by cysteine, an amino acid with dissimilar properties. In a functional study using Saccharomyces cerevisiae yeast, this alteration was found to confer a pronounced loss of mismatch repair function (Ellison AR et al. Nucleic Acids Res., 2004 Oct;32:5321-38). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). 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: Sep 29, 2024

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