NM_000249.4(MLH1):c.554T>G (p.Val185Gly) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 19, 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:: RCV000218149.2

Allele description [Variation Report for NM_000249.4(MLH1):c.554T>G (p.Val185Gly)]

NM_000249.4(MLH1):c.554T>G (p.Val185Gly)

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.554T>G (p.Val185Gly)

HGVS:

NC_000003.12:g.37011828T>G
NG_007109.2:g.23479T>G
NM_000249.4:c.554T>GMANE SELECT
NM_001167617.3:c.260T>G
NM_001167618.3:c.-170T>G
NM_001167619.3:c.-170T>G
NM_001258271.2:c.554T>G
NM_001258273.2:c.-170T>G
NM_001258274.3:c.-170T>G
NM_001354615.2:c.-170T>G
NM_001354616.2:c.-170T>G
NM_001354617.2:c.-170T>G
NM_001354618.2:c.-170T>G
NM_001354619.2:c.-170T>G
NM_001354620.2:c.260T>G
NM_001354621.2:c.-263T>G
NM_001354622.2:c.-376T>G
NM_001354623.2:c.-376T>G
NM_001354624.2:c.-273T>G
NM_001354625.2:c.-273T>G
NM_001354626.2:c.-273T>G
NM_001354627.2:c.-273T>G
NM_001354628.2:c.554T>G
NM_001354629.2:c.455T>G
NM_001354630.2:c.554T>G
NP_000240.1:p.Val185Gly
NP_000240.1:p.Val185Gly
NP_001161089.1:p.Val87Gly
NP_001245200.1:p.Val185Gly
NP_001341549.1:p.Val87Gly
NP_001341557.1:p.Val185Gly
NP_001341558.1:p.Val152Gly
NP_001341559.1:p.Val185Gly
LRG_216t1:c.554T>G
LRG_216:g.23479T>G
LRG_216p1:p.Val185Gly
NC_000003.11:g.37053319T>G
NM_000249.3:c.554T>G
NM_001167618.1:c.-170T>G
P40692:p.Val185Gly

Protein change:

V152G

Links:

UniProtKB: P40692#VAR_004447; dbSNP: rs63750515

NCBI 1000 Genomes Browser:

rs63750515

Molecular consequence:

NM_001167618.3:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-170T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-263T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-376T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-376T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-273T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-273T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-273T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-273T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.554T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.260T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.554T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.260T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.554T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.455T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.554T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000279073	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 19, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000279073

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 19, 2020)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000279073.9

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

Description

Published functional studies demonstrate a damaging effect: reduced protein expression, deficient MMR activity, abnormal subcellular localization, and reduced interaction with protein partners (Trojan 2002, Kondo 2003, Raevaara 2005, Takahashi 2007, Bouvet 2019); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with personal and family history of MLH1-associated cancers including those with tumor studies consistent with pathogenic variants in this gene (Kohonen-Corish 1996, Scott 2001, Raevaara 2005, Chao 2008, Toon 2013, Chubb 2015); This variant is associated with the following publications: (PMID: 11112663, 30212499, 12810663, 17594722, 21120944, 22949387, 24362816, 9697702, 25525159, 16083711, 17510385, 11781295, 18383312, 25559809, 17192056, 30998989, 8808596, 23797718)

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

Last Updated: Aug 11, 2024

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