NM_000249.4(MLH1):c.191A>G (p.Asn64Ser) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 28, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV002288569.7

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]

Observations:

Condition(s)

Name:: Colorectal cancer, hereditary nonpolyposis, type 2 (LYNCH2)
Synonyms:: COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 2; Lynch syndrome II; MLH1-Related Lynch Syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012249; MedGen: C1333991; Orphanet: 144; OMIM: 609310

Recent activity

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gi|330443362|ref|NP_009341.2|

Protein
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Gene
homo sapiens[Organism] AND VSIG8 AND (alive[prop]) (121)
Gene
uncharacterized protein LOC111495163 [Cucurbita maxima]
uncharacterized protein LOC111495163 [Cucurbita maxima]
gi|1280980783|ref|XP_023000836.1|

Protein
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alpha-dioxygenase 2 isoform X1 [Benincasa hispida]
gi|1955843216|ref|XP_038879582.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002581763	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 8, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004018166	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely benign (Mar 15, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004195090	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 28, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002581763

MGZ Medical Genetics Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 8, 2022)

germline

clinical testing

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

SCV004018166

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Likely benign
(Mar 15, 2023)

unknown

clinical testing

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

Citation Link,

SCV004195090

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 28, 2024)

unknown

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes.

Pruss D, Morris B, Hughes E, Eggington JM, Esterling L, Robinson BS, van Kan A, Fernandes PH, Roa BB, Gutin A, Wenstrup RJ, Bowles KR.

Breast Cancer Res Treat. 2014 Aug;147(1):119-32. doi: 10.1007/s10549-014-3065-9. Epub 2014 Aug 2.

PubMed [citation]

PMID:: 25085752

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From MGZ Medical Genetics Center, SCV002581763.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

#	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		3	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004018166.1

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

Description

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

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

From Baylor Genetics, SCV004195090.2

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

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

Last Updated: Oct 20, 2024

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