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NM_000249.4(MLH1):c.626A>G (p.Asn209Ser) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:
Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:
Oct 16, 2023
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:
RCV000662374.6

Allele description [Variation Report for NM_000249.4(MLH1):c.626A>G (p.Asn209Ser)]

NM_000249.4(MLH1):c.626A>G (p.Asn209Ser)

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.626A>G (p.Asn209Ser)
HGVS:
  • NC_000003.12:g.37012048A>G
  • NG_007109.2:g.23699A>G
  • NM_000249.4:c.626A>GMANE SELECT
  • NM_001167617.3:c.332A>G
  • NM_001167618.3:c.-98A>G
  • NM_001167619.3:c.-98A>G
  • NM_001258271.2:c.626A>G
  • NM_001258273.2:c.-98A>G
  • NM_001258274.3:c.-98A>G
  • NM_001354615.2:c.-98A>G
  • NM_001354616.2:c.-98A>G
  • NM_001354617.2:c.-98A>G
  • NM_001354618.2:c.-98A>G
  • NM_001354619.2:c.-98A>G
  • NM_001354620.2:c.332A>G
  • NM_001354621.2:c.-191A>G
  • NM_001354622.2:c.-304A>G
  • NM_001354623.2:c.-304A>G
  • NM_001354624.2:c.-201A>G
  • NM_001354625.2:c.-201A>G
  • NM_001354626.2:c.-201A>G
  • NM_001354627.2:c.-201A>G
  • NM_001354628.2:c.626A>G
  • NM_001354629.2:c.527A>G
  • NM_001354630.2:c.626A>G
  • NP_000240.1:p.Asn209Ser
  • NP_000240.1:p.Asn209Ser
  • NP_001161089.1:p.Asn111Ser
  • NP_001245200.1:p.Asn209Ser
  • NP_001341549.1:p.Asn111Ser
  • NP_001341557.1:p.Asn209Ser
  • NP_001341558.1:p.Asn176Ser
  • NP_001341559.1:p.Asn209Ser
  • LRG_216t1:c.626A>G
  • LRG_216:g.23699A>G
  • LRG_216p1:p.Asn209Ser
  • NC_000003.11:g.37053539A>G
  • NM_000249.3:c.626A>G
  • p.N209S
Protein change:
N111S
Links:
dbSNP: rs150478207
NCBI 1000 Genomes Browser:
rs150478207
Molecular consequence:
  • NM_001167618.3:c.-98A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-98A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-98A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-98A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-98A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-98A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-98A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-98A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-98A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-191A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-304A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-304A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-201A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-201A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-201A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-201A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000249.4:c.626A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.332A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.626A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.332A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.626A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.527A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.626A>G - missense variant - [Sequence Ontology: SO:0001583]

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000784768Counsyl
criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))
Uncertain significance
(Apr 27, 2017)
unknownclinical testing

Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf,

Citation Link,

SCV001136380Mendelics
criteria provided, single submitter

(Mendelics Assertion Criteria 2017)
Uncertain significance
(May 28, 2019)
unknownclinical testing

Citation Link,

SCV004018109Myriad Genetics, Inc.
criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))
Likely benign
(Mar 13, 2023)
unknownclinical testing

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

Citation Link,

SCV004171471St. Jude Molecular Pathology, St. Jude Children's Research Hospital
criteria provided, single submitter

(St. Jude Assertion Criteria 2020)
Uncertain significance
(Oct 16, 2023)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Details of each submission

From Counsyl, SCV000784768.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Mendelics, SCV001136380.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Myriad Genetics, Inc., SCV004018109.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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].

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV004171471.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The MLH1 c.626A>G (p.Asn209Ser) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with ovarian cancer (PMID: 23047549). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024