NM_000249.4(MLH1):c.126A>C (p.Ala42=) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Jul 5, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000773818.4

Allele description [Variation Report for NM_000249.4(MLH1):c.126A>C (p.Ala42=)]

NM_000249.4(MLH1):c.126A>C (p.Ala42=)

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.126A>C (p.Ala42=)

HGVS:

NC_000003.12:g.36996628A>C
NG_007109.2:g.8279A>C
NG_008418.1:g.1677T>G
NM_000249.4:c.126A>CMANE SELECT
NM_001167617.3:c.-164A>C
NM_001167618.3:c.-598A>C
NM_001167619.3:c.-506A>C
NM_001258271.2:c.126A>C
NM_001258273.2:c.-517+2965A>C
NM_001258274.3:c.-743A>C
NM_001354615.2:c.-501A>C
NM_001354616.2:c.-506A>C
NM_001354617.2:c.-598A>C
NM_001354618.2:c.-598A>C
NM_001354619.2:c.-598A>C
NM_001354620.2:c.-164A>C
NM_001354621.2:c.-691A>C
NM_001354622.2:c.-804A>C
NM_001354623.2:c.-723+2738A>C
NM_001354624.2:c.-701A>C
NM_001354625.2:c.-604A>C
NM_001354626.2:c.-701A>C
NM_001354627.2:c.-701A>C
NM_001354628.2:c.126A>C
NM_001354629.2:c.126A>C
NM_001354630.2:c.126A>C
NP_000240.1:p.Ala42=
NP_000240.1:p.Ala42=
NP_001245200.1:p.Ala42=
NP_001341557.1:p.Ala42=
NP_001341558.1:p.Ala42=
NP_001341559.1:p.Ala42=
LRG_216t1:c.126A>C
LRG_216:g.8279A>C
LRG_216p1:p.Ala42=
NC_000003.11:g.37038119A>C
NM_000249.3:c.126A>C

Links:

dbSNP: rs1385176857

NCBI 1000 Genomes Browser:

rs1385176857

Molecular consequence:

NM_001167617.3:c.-164A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-598A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-506A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-743A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-501A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-506A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-598A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-598A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-598A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-164A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-691A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-804A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-701A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-604A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-701A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-701A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+2965A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2738A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.126A>C - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001258271.2:c.126A>C - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354628.2:c.126A>C - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354629.2:c.126A>C - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354630.2:c.126A>C - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

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interleukin 8 (74079)
PMC
endoglucanase 24 [Jatropha curcas]
endoglucanase 24 [Jatropha curcas]
gi|802708133|ref|XP_012084447.1|

Protein
PREDICTED: Homo sapiens leucine zipper protein 2 (LUZP2), transcript variant X3,...
PREDICTED: Homo sapiens leucine zipper protein 2 (LUZP2), transcript variant X3, mRNA
gi|1370459246|ref|XM_017017649.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000907518	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Aug 28, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002683478	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Jul 5, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000907518

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Aug 28, 2018)

germline

clinical testing

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

SCV002683478

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Jul 5, 2022)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 Color Diagnostics, LLC DBA Color Health, SCV000907518.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002683478.2

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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: May 1, 2024

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