NM_000249.4(MLH1):c.103A>G (p.Met35Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 12, 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:: RCV000221696.1

Allele description [Variation Report for NM_000249.4(MLH1):c.103A>G (p.Met35Val)]

NM_000249.4(MLH1):c.103A>G (p.Met35Val)

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.103A>G (p.Met35Val)

HGVS:

NC_000003.12:g.36993650A>G
NG_007109.2:g.5301A>G
NG_008418.1:g.4655T>C
NM_000249.4:c.103A>GMANE SELECT
NM_001167617.3:c.-414A>G
NM_001167618.3:c.-843A>G
NM_001167619.3:c.-756A>G
NM_001258271.2:c.103A>G
NM_001258273.2:c.-530A>G
NM_001258274.3:c.-993A>G
NM_001354615.2:c.-524A>G
NM_001354616.2:c.-524A>G
NM_001354617.2:c.-616A>G
NM_001354618.2:c.-848A>G
NM_001354619.2:c.-972A>G
NM_001354620.2:c.-182A>G
NM_001354621.2:c.-941A>G
NM_001354622.2:c.-1054A>G
NM_001354623.2:c.-963A>G
NM_001354624.2:c.-724A>G
NM_001354625.2:c.-622A>G
NM_001354626.2:c.-719A>G
NM_001354627.2:c.-951A>G
NM_001354628.2:c.103A>G
NM_001354629.2:c.103A>G
NM_001354630.2:c.103A>G
NP_000240.1:p.Met35Val
NP_000240.1:p.Met35Val
NP_001245200.1:p.Met35Val
NP_001341557.1:p.Met35Val
NP_001341558.1:p.Met35Val
NP_001341559.1:p.Met35Val
LRG_216t1:c.103A>G
LRG_216:g.5301A>G
LRG_216p1:p.Met35Val
NC_000003.11:g.37035141A>G
NM_000249.3:c.103A>G

Protein change:

M35V

Links:

dbSNP: rs876659691

NCBI 1000 Genomes Browser:

rs876659691

Molecular consequence:

NM_001167617.3:c.-414A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-843A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-756A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-530A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-993A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-524A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-524A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-616A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-848A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-972A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-182A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-941A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-1054A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-963A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-724A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-622A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-719A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-951A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.103A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.103A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.103A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.103A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.103A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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PREDICTED: Cucurbita moschata mitochondrial carnitine/acylcarnitine carrier-like...
PREDICTED: Cucurbita moschata mitochondrial carnitine/acylcarnitine carrier-like protein (LOC111464063), mRNA
gi|1279820304|ref|XM_023108120.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000276414	Ambry Genetics	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015))	Uncertain significance (Jun 12, 2015)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000276414

Ambry Genetics

criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (10/2015))

Uncertain significance
(Jun 12, 2015)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Details of each submission

From Ambry Genetics, SCV000276414.5

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

Description

The p.M35V variant (also known as c.103A>G), located in coding exon 1 of the MLH1 gene, results from an A to G substitution at nucleotide position 103. The methionine at codon 35 is replaced by valine, an amino acid with highly similar properties. A similar alteration at this position, p.M35R,has been classified as pathogenicby multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). The p.M35R alteration, which is involved in theATP-binding pocket, showed defectsin two different functional assays(Takahashiet al. Cancer Res.2007May15;67(10):4595-604).The p.M35Vvariant 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 0.002% (greater than 65000alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebratespecies.In addition, this alteration is predicted to be benign byPolyPhen butdeleterious bySIFT in silico analyses.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 still limited at this time, the clinical significance of p.M35V remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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