NM_000249.4(MLH1):c.2135G>C (p.Trp712Ser) AND not provided

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 17, 2017
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:: RCV000586210.1

Allele description [Variation Report for NM_000249.4(MLH1):c.2135G>C (p.Trp712Ser)]

NM_000249.4(MLH1):c.2135G>C (p.Trp712Ser)

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.2135G>C (p.Trp712Ser)

HGVS:

NC_000003.12:g.37050517G>C
NG_007109.2:g.62168G>C
NM_000249.4:c.2135G>CMANE SELECT
NM_001167617.3:c.1841G>C
NM_001167618.3:c.1412G>C
NM_001167619.3:c.1412G>C
NM_001258271.2:c.1928G>C
NM_001258273.2:c.1412G>C
NM_001258274.3:c.1412G>C
NM_001354615.2:c.1412G>C
NM_001354616.2:c.1412G>C
NM_001354617.2:c.1412G>C
NM_001354618.2:c.1412G>C
NM_001354619.2:c.1412G>C
NM_001354620.2:c.1841G>C
NM_001354621.2:c.1112G>C
NM_001354622.2:c.1112G>C
NM_001354623.2:c.1112G>C
NM_001354624.2:c.1061G>C
NM_001354625.2:c.1061G>C
NM_001354626.2:c.1061G>C
NM_001354627.2:c.1061G>C
NM_001354628.2:c.2042G>C
NM_001354629.2:c.2036G>C
NM_001354630.2:c.1970G>C
NP_000240.1:p.Trp712Ser
NP_000240.1:p.Trp712Ser
NP_001161089.1:p.Trp614Ser
NP_001161090.1:p.Trp471Ser
NP_001161091.1:p.Trp471Ser
NP_001245200.1:p.Trp643Ser
NP_001245202.1:p.Trp471Ser
NP_001245203.1:p.Trp471Ser
NP_001341544.1:p.Trp471Ser
NP_001341545.1:p.Trp471Ser
NP_001341546.1:p.Trp471Ser
NP_001341547.1:p.Trp471Ser
NP_001341548.1:p.Trp471Ser
NP_001341549.1:p.Trp614Ser
NP_001341550.1:p.Trp371Ser
NP_001341551.1:p.Trp371Ser
NP_001341552.1:p.Trp371Ser
NP_001341553.1:p.Trp354Ser
NP_001341554.1:p.Trp354Ser
NP_001341555.1:p.Trp354Ser
NP_001341556.1:p.Trp354Ser
NP_001341557.1:p.Trp681Ser
NP_001341558.1:p.Trp679Ser
NP_001341559.1:p.Trp657Ser
LRG_216t1:c.2135G>C
LRG_216:g.62168G>C
LRG_216p1:p.Trp712Ser
NC_000003.11:g.37092008G>C
NM_000249.3:c.2135G>C

Protein change:

W354S

Links:

dbSNP: rs63750561

NCBI 1000 Genomes Browser:

rs63750561

Molecular consequence:

NM_000249.4:c.2135G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1841G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1412G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1412G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1928G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1412G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1412G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1412G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1412G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1412G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1412G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1412G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1841G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1112G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1112G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1112G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1061G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1061G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1061G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1061G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.2042G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.2036G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1970G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000696147	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 17, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000696147

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Feb 17, 2017)

germline

clinical testing

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

LabCorp Variant Classification Summary - May 2015.docx

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

Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.

Hardt K, Heick SB, Betz B, Goecke T, Yazdanparast H, Küppers R, Servan K, Steinke V, Rahner N, Morak M, Holinski-Feder E, Engel C, Möslein G, Schackert HK, von Knebel Doeberitz M, Pox C; Peter Propping.; German HNPCC consortium., Hegemann JH, Royer-Pokora B.

Fam Cancer. 2011 Jun;10(2):273-84. doi: 10.1007/s10689-011-9431-4.

PubMed [citation]

PMID:: 21404117

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696147.1

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

Description

Variant summary: The MLH1 c.2135G>C (p.Trp712Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may create SC35 and SF2/ASF ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant is absent in the large control database ExAC (0/121230 control chromosomes). Overall, there were very few data points in the literature and databases regarding this variant. Taken together, this variant is classified as VUS.

#	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: Nov 5, 2022

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