rs175081

Variant names:

• chr14-75047180-T-C
• rs175081
• NM_001040108.2:c.2476A>G
• MLH3 p.Asn826Asp

Your query was ambiguous. Multiple possible variants found:

• chr14-75047180-T-C
• chr14-75047180-T-A
• chr14-75047180-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040108.2(MLH3):​c.2476A>G​(p.Asn826Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,614,180 control chromosomes in the GnomAD database, including 803,856 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N826N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.99 (74524 hom., cov: 32)
  • Exomes 𝑓: 1.0 (729332 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.319
• Publications: 45 publications found

Genes affected

MLH3 (HGNC:7128): (mutL homolog 3) This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

MLH3 Gene-Disease associations (from GenCC):

• colorectal cancer, hereditary nonpolyposis, type 7

  Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Laboratory for Molecular Medicine
• intestinal polyposis syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6601552E-6).
• BP6: Variant 14-75047180-T-C is Benign according to our data. Variant chr14-75047180-T-C is described in ClinVar as Benign. ClinVar VariationId is 257251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	NM_001040108.2	MANE Select	c.2476A>G	p.Asn826Asp	missense	Exon 2 of 13	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.2476A>G	p.Asn826Asp	missense	Exon 2 of 12	NP_055196.2	Q9UHC1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	ENST00000355774.7	TSL:5 MANE Select	c.2476A>G	p.Asn826Asp	missense	Exon 2 of 13	ENSP00000348020.2	Q9UHC1-1
	MLH3	ENST00000380968.6	TSL:1	c.2476A>G	p.Asn826Asp	missense	Exon 2 of 12	ENSP00000370355.3	Q9UHC1-2
	MLH3	ENST00000930871.1		c.2476A>G	p.Asn826Asp	missense	Exon 2 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes AF: 0.989 AC: 150566 AN: 152240 Hom.: 74466 Cov.: 32

Gnomad AFR AF: 0.962

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.989

GnomAD2 exomes AF: 0.997 AC: 250717 AN: 251402 AF XY: 0.998

Gnomad AFR exome AF: 0.963

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.999 AC: 1460221 AN: 1461822 Hom.: 729332 Cov.: 51 AF XY: 0.999 AC XY: 726535 AN XY: 727214

African (AFR) AF: 0.961 AC: 32187 AN: 33480

American (AMR) AF: 0.998 AC: 44644 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26132 AN: 26132

East Asian (EAS) AF: 1.00 AC: 39684 AN: 39684

South Asian (SAS) AF: 1.00 AC: 86239 AN: 86252

European-Finnish (FIN) AF: 1.00 AC: 53406 AN: 53406

Middle Eastern (MID) AF: 0.997 AC: 5753 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111941 AN: 1111982

Other (OTH) AF: 0.997 AC: 60235 AN: 60394

GnomAD4 genome AF: 0.989 AC: 150683 AN: 152358 Hom.: 74524 Cov.: 32 AF XY: 0.989 AC XY: 73704 AN XY: 74506

African (AFR) AF: 0.962 AC: 39991 AN: 41582

American (AMR) AF: 0.997 AC: 15254 AN: 15306

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5187 AN: 5188

South Asian (SAS) AF: 1.00 AC: 4826 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10622 AN: 10622

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68032 AN: 68040

Other (OTH) AF: 0.990 AC: 2094 AN: 2116

Alfa AF: 0.995 Hom.: 149227

Bravo AF: 0.987

Asia WGS AF: 0.999 AC: 3475 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Colorectal cancer, hereditary nonpolyposis, type 7 (3)
-	-	2	not provided (2)
-	-	1	Endometrial carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.40
DANN	Benign	0.69
DEOGEN2	Benign	0.089	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.034	T
MetaRNN	Benign	0.0000017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.32
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.14
Sift	Benign	0.85	T
Sift4G	Benign	0.85	T
PromoterAI		0.082	Neutral
Varity_R		0.041
gMVP		0.094
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs175081;

hg19: chr14-75513883;

COSMIC: COSV107260146;

COSMIC: COSV107260146;