NM_000249.4(MLH1):c.1652A>C (p.Asn551Thr) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Jun 17, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000249.4(MLH1):c.1652A>C (p.Asn551Thr)]

NM_000249.4(MLH1):c.1652A>C (p.Asn551Thr)

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.1652A>C (p.Asn551Thr)
  • NC_000003.12:g.37040279A>C
  • NG_007109.2:g.51930A>C
  • NM_000249.4:c.1652A>CMANE SELECT
  • NM_001167617.3:c.1358A>C
  • NM_001167618.3:c.929A>C
  • NM_001167619.3:c.929A>C
  • NM_001258271.2:c.1652A>C
  • NM_001258273.2:c.929A>C
  • NM_001258274.3:c.929A>C
  • NM_001354615.2:c.929A>C
  • NM_001354616.2:c.929A>C
  • NM_001354617.2:c.929A>C
  • NM_001354618.2:c.929A>C
  • NM_001354619.2:c.929A>C
  • NM_001354620.2:c.1358A>C
  • NM_001354621.2:c.629A>C
  • NM_001354622.2:c.629A>C
  • NM_001354623.2:c.629A>C
  • NM_001354624.2:c.578A>C
  • NM_001354625.2:c.578A>C
  • NM_001354626.2:c.578A>C
  • NM_001354627.2:c.578A>C
  • NM_001354628.2:c.1652A>C
  • NM_001354629.2:c.1553A>C
  • NM_001354630.2:c.1652A>C
  • NP_000240.1:p.Asn551Thr
  • NP_000240.1:p.Asn551Thr
  • NP_001161089.1:p.Asn453Thr
  • NP_001161090.1:p.Asn310Thr
  • NP_001161091.1:p.Asn310Thr
  • NP_001245200.1:p.Asn551Thr
  • NP_001245202.1:p.Asn310Thr
  • NP_001245203.1:p.Asn310Thr
  • NP_001341544.1:p.Asn310Thr
  • NP_001341545.1:p.Asn310Thr
  • NP_001341546.1:p.Asn310Thr
  • NP_001341547.1:p.Asn310Thr
  • NP_001341548.1:p.Asn310Thr
  • NP_001341549.1:p.Asn453Thr
  • NP_001341550.1:p.Asn210Thr
  • NP_001341551.1:p.Asn210Thr
  • NP_001341552.1:p.Asn210Thr
  • NP_001341553.1:p.Asn193Thr
  • NP_001341554.1:p.Asn193Thr
  • NP_001341555.1:p.Asn193Thr
  • NP_001341556.1:p.Asn193Thr
  • NP_001341557.1:p.Asn551Thr
  • NP_001341558.1:p.Asn518Thr
  • NP_001341559.1:p.Asn551Thr
  • LRG_216t1:c.1652A>C
  • LRG_216:g.51930A>C
  • LRG_216p1:p.Asn551Thr
  • NC_000003.11:g.37081770A>C
  • NM_000249.3:c.1652A>C
  • P40692:p.Asn551Thr
Protein change:
UniProtKB: P40692#VAR_012922; dbSNP: rs63750271
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000249.4:c.1652A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.1358A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.929A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.929A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.1652A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.929A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.929A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.929A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.929A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.929A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.929A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.929A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.1358A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354621.2:c.629A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354622.2:c.629A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354623.2:c.629A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354624.2:c.578A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354625.2:c.578A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354626.2:c.578A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354627.2:c.578A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.1652A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.1553A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.1652A>C - missense variant - [Sequence Ontology: SO:0001583]


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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001173046Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Sep 25, 2018)
germlineclinical testing

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

Citation Link,

SCV001344558Color Health, Inccriteria provided, single submitter
Uncertain significance
(Jun 17, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Mutations within the hMLH1 and hPMS2 subunits of the human MutLalpha mismatch repair factor affect its ATPase activity, but not its ability to interact with hMutSalpha.

Räschle M, Dufner P, Marra G, Jiricny J.

J Biol Chem. 2002 Jun 14;277(24):21810-20. Epub 2002 Apr 10.

PubMed [citation]

Differential rates of frameshift alterations in four repeat sequences of hereditary nonpolyposis colorectal cancer tumors.

Paoloni-Giacobino A, Rey-Berthod C, Couturier A, Antonarakis SE, Hutter P.

Hum Genet. 2002 Sep;111(3):284-9. Epub 2002 Aug 6.

PubMed [citation]
See all PubMed Citations (13)

Details of each submission

From Ambry Genetics, SCV001173046.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (12)


The p.N551T variant (also known as c.1652A>C), located in coding exon 14 of the MLH1 gene, results from an A to C substitution at nucleotide position 1652. The asparagine at codon 551 is replaced by threonine, an amino acid with similar properties. This alteration was identified in a Swiss proband diagnosed with colorectal cancer as well as stomach cancer at age 46 whose family history met Amsterdam criteria for Lynch syndrome and tumor demonstrated high microsatellite instability (MSI-H) (Hutter P et al. Int. J. Cancer, 1998 Dec;78:680-4). This alteration was also identified in a Saudi Arabian proband with a MSI-H colorectal tumor who met Amsterdam criteria for Lynch syndrome (Siraj AK et al. Cancer, 2015 Jun;121:1762-71). In a large consanguineous Turkish family that met Amsterdam criteria for Lynch syndrome, this alteration segregated with disease in 5 individuals affected with colorectal cancer, two of whom were obligate carriers (Wang Q et al. Int. J. Cancer, 1997 Dec;73:831-6). In two in vitro mismatch repair (MMR) complementation assays, this variant demonstrated proficient MMR activity and interaction with PMS2 was intact in a co-immunoprecipitation study (Takahashi M et al. Cancer Res., 2007 May;67:4595-604; Kosinski J et al. Hum. Mutat., 2010 Aug;31:975-82; Hinrichsen I et al. Clin. Cancer Res., 2013 May;19:2432-41). However, in reversion assays performed in yeast, no dominant mutator effect was seen with this variant (Takahashi M et al. Cancer Res., 2007 May;67:4595-604). Also, although expression levels were variable, several studies report reduced relative expression in human cell lines by Western blotting for this variant (Takahashi M et al. Cancer Res., 2007 May;67:4595-604; Kosinski J et al. Hum. Mutat., 2010 Aug;31:975-82; Hinrichsen I et al. Clin. Cancer Res., 2013 May;19:2432-41). Furthermore, this variant did not demonstrate a deleterious effect on splicing by mini gene assay or by RT-PCR using patient RNA (Auclair J et al. Hum. Mutat., 2006 Feb;27:145-54; Tournier I et al. Hum. Mutat., 2008 Dec;29:1412-24). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analysis (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV001344558.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 4, 2021

Support Center