NM_000249.4(MLH1):c.191A>G (p.Asn64Ser) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 29, 2024
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:: RCV000075426.13

Allele description [Variation Report for NM_000249.4(MLH1):c.191A>G (p.Asn64Ser)]

NM_000249.4(MLH1):c.191A>G (p.Asn64Ser)

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.191A>G (p.Asn64Ser)

Other names:

p.N64S:AAT>AGT

HGVS:

NC_000003.12:g.36996693A>G
NG_007109.2:g.8344A>G
NG_008418.1:g.1612T>C
NM_000249.4:c.191A>GMANE SELECT
NM_001167617.3:c.-99A>G
NM_001167618.3:c.-533A>G
NM_001167619.3:c.-441A>G
NM_001258271.2:c.191A>G
NM_001258273.2:c.-517+3030A>G
NM_001258274.3:c.-678A>G
NM_001354615.2:c.-436A>G
NM_001354616.2:c.-441A>G
NM_001354617.2:c.-533A>G
NM_001354618.2:c.-533A>G
NM_001354619.2:c.-533A>G
NM_001354620.2:c.-99A>G
NM_001354621.2:c.-626A>G
NM_001354622.2:c.-739A>G
NM_001354623.2:c.-723+2803A>G
NM_001354624.2:c.-636A>G
NM_001354625.2:c.-539A>G
NM_001354626.2:c.-636A>G
NM_001354627.2:c.-636A>G
NM_001354628.2:c.191A>G
NM_001354629.2:c.191A>G
NM_001354630.2:c.191A>G
NP_000240.1:p.Asn64Ser
NP_000240.1:p.Asn64Ser
NP_001245200.1:p.Asn64Ser
NP_001341557.1:p.Asn64Ser
NP_001341558.1:p.Asn64Ser
NP_001341559.1:p.Asn64Ser
LRG_216t1:c.191A>G
LRG_216:g.8344A>G
LRG_216p1:p.Asn64Ser
NC_000003.11:g.37038184A>G
NM_000249.3:c.191A>G
P40692:p.Asn64Ser

Protein change:

N64S

Links:

UniProtKB: P40692#VAR_004438; dbSNP: rs63750952

NCBI 1000 Genomes Browser:

rs63750952

Molecular consequence:

NM_001167617.3:c.-99A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-533A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-441A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-678A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-436A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-441A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-533A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-533A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-533A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-99A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-626A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-739A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-636A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-539A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-636A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-636A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3030A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2803A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.191A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.191A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.191A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.191A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.191A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary nonpolyposis colorectal neoplasms
Identifiers:: MeSH: D003123; MedGen: C0009405

Recent activity

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homo sapiens[Organism] AND CCDC19 AND (alive[prop]) (3)
Gene
uncharacterized protein LOC111477668 [Cucurbita maxima]
uncharacterized protein LOC111477668 [Cucurbita maxima]
gi|1280973467|ref|XP_022977309.1|

Protein
inorganic pyrophosphatase TTM2 isoform X2 [Cucumis melo]
inorganic pyrophosphatase TTM2 isoform X2 [Cucumis melo]
gi|659091356|ref|XP_008446505.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000218899	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 9311737, 16736289, 26552419, 28514183, 28767289, 28888541, 31332305, 17135187, 17510385, 21404117, 30504929, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000218899

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 29, 2024)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

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

Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations.

Wijnen J, Khan PM, Vasen H, van der Klift H, Mulder A, van Leeuwen-Cornelisse I, Bakker B, Losekoot M, Møller P, Fodde R.

Am J Hum Genet. 1997 Aug;61(2):329-35.

PubMed [citation]

PMID:: 9311737
PMCID:: PMC1715907

Germline mutations of the hMLH1 and hMSH2 mismatch repair genes in Belgian hereditary nonpolyposis colon cancer (HNPCC) patients.

Spaepen M, Vankeirsbilck B, Van Opstal S, Tejpar S, Van Cutsem E, Geboes K, Legius E, Matthijs G.

Fam Cancer. 2006;5(2):179-89.

PubMed [citation]

PMID:: 16736289

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000218899.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 64 of the MLH1 protein (p.Asn64Ser). This variant is present in population databases (rs63750952, gnomAD 0.006%). This missense change has been observed in individual(s) with colorectal, endometrial, pancreatic, ovarian cancer and/or Lynch syndrome (PMID: 9311737, 16736289, 21404117, 26552419, 28514183, 28767289, 28888541, 31332305). ClinVar contains an entry for this variant (Variation ID: 89947). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 17135187, 17510385, 21404117, 30504929). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of 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: Oct 20, 2024

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