NM_000249.4(MLH1):c.2074T>C (p.Ser692Pro) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 24, 2022
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:: RCV002509223.1

Allele description [Variation Report for NM_000249.4(MLH1):c.2074T>C (p.Ser692Pro)]

NM_000249.4(MLH1):c.2074T>C (p.Ser692Pro)

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.2074T>C (p.Ser692Pro)

Other names:

p.S692P:TCT>CCT

HGVS:

NC_000003.12:g.37048988T>C
NG_007109.2:g.60639T>C
NM_000249.4:c.2074T>CMANE SELECT
NM_001167617.3:c.1780T>C
NM_001167618.3:c.1351T>C
NM_001167619.3:c.1351T>C
NM_001258271.2:c.1896+1305T>C
NM_001258273.2:c.1351T>C
NM_001258274.3:c.1351T>C
NM_001354615.2:c.1351T>C
NM_001354616.2:c.1351T>C
NM_001354617.2:c.1351T>C
NM_001354618.2:c.1351T>C
NM_001354619.2:c.1351T>C
NM_001354620.2:c.1780T>C
NM_001354621.2:c.1051T>C
NM_001354622.2:c.1051T>C
NM_001354623.2:c.1051T>C
NM_001354624.2:c.1000T>C
NM_001354625.2:c.1000T>C
NM_001354626.2:c.1000T>C
NM_001354627.2:c.1000T>C
NM_001354628.2:c.1981T>C
NM_001354629.2:c.1975T>C
NM_001354630.2:c.1909T>C
NP_000240.1:p.Ser692Pro
NP_000240.1:p.Ser692Pro
NP_001161089.1:p.Ser594Pro
NP_001161090.1:p.Ser451Pro
NP_001161091.1:p.Ser451Pro
NP_001245202.1:p.Ser451Pro
NP_001245203.1:p.Ser451Pro
NP_001341544.1:p.Ser451Pro
NP_001341545.1:p.Ser451Pro
NP_001341546.1:p.Ser451Pro
NP_001341547.1:p.Ser451Pro
NP_001341548.1:p.Ser451Pro
NP_001341549.1:p.Ser594Pro
NP_001341550.1:p.Ser351Pro
NP_001341551.1:p.Ser351Pro
NP_001341552.1:p.Ser351Pro
NP_001341553.1:p.Ser334Pro
NP_001341554.1:p.Ser334Pro
NP_001341555.1:p.Ser334Pro
NP_001341556.1:p.Ser334Pro
NP_001341557.1:p.Ser661Pro
NP_001341558.1:p.Ser659Pro
NP_001341559.1:p.Ser637Pro
LRG_216t1:c.2074T>C
LRG_216:g.60639T>C
LRG_216p1:p.Ser692Pro
NC_000003.11:g.37090479T>C
NM_000249.3:c.2074T>C

Protein change:

S334P

Links:

dbSNP: rs587779957

NCBI 1000 Genomes Browser:

rs587779957

Molecular consequence:

NM_001258271.2:c.1896+1305T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.2074T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1780T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1780T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.1051T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.1051T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.1051T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.1000T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.1000T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.1000T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.1000T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1981T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1975T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1909T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002819786	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Dec 24, 2022)	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

SCV002819786

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Dec 24, 2022)

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

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry..

JAMA. 2005 Feb 16;293(7):799-809.

PubMed [citation]

PMID:: 15713769
PMCID:: PMC2933041

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002819786.1

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

Description

Variant summary: MLH1 c.2074T>C (p.Ser692Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251112 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2074T>C has been reported in the literature as a VUS in at-least one individual among colorectal cancer cases from HNPCC Amsterdam 1 criteria families with defective mismatch repair and protein expression reported as - MLH1 and MSH2 intact (example, Casey_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories and an expert panel (INSIGHT) reported the variant with conflicting assessments (VUS, n=2; LB/B, n=2 including the expert panel). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: Aug 11, 2024

ClinVar

Relating variation to medicine