rs28756988

Variant names:

• chr14-75047497-T-C
• rs28756988
• NM_001040108.2:c.2159A>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.2159A>G​(p.Tyr720Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,614,094 control chromosomes in the GnomAD database, including 386 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y720Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.027 (219 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (167 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.0840
• Publications: 7 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: ClinGen, Ambry Genetics, 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=0.0017614067).
• BP6: Variant 14-75047497-T-C is Benign according to our data. Variant chr14-75047497-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 314386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0928 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.2159A>G	p.Tyr720Cys	missense	Exon 2 of 13	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.2159A>G	p.Tyr720Cys	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.2159A>G	p.Tyr720Cys	missense	Exon 2 of 13	ENSP00000348020.2	Q9UHC1-1
	MLH3	ENST00000380968.6	TSL:1	c.2159A>G	p.Tyr720Cys	missense	Exon 2 of 12	ENSP00000370355.3	Q9UHC1-2
	MLH3	ENST00000930871.1		c.2159A>G	p.Tyr720Cys	missense	Exon 2 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4162 AN: 152188 Hom.: 219 Cov.: 33

Gnomad AFR AF: 0.0954

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00975

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00711 AC: 1788 AN: 251336 AF XY: 0.00518

Gnomad AFR exome AF: 0.0992

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00276 AC: 4038 AN: 1461788 Hom.: 167 Cov.: 35 AF XY: 0.00231 AC XY: 1681 AN XY: 727192

African (AFR) AF: 0.101 AC: 3393 AN: 33470

American (AMR) AF: 0.00425 AC: 190 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0000746 AC: 83 AN: 1111984

Other (OTH) AF: 0.00538 AC: 325 AN: 60392

GnomAD4 genome AF: 0.0274 AC: 4166 AN: 152306 Hom.: 219 Cov.: 33 AF XY: 0.0260 AC XY: 1936 AN XY: 74478

African (AFR) AF: 0.0952 AC: 3957 AN: 41544

American (AMR) AF: 0.00973 AC: 149 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68024

Other (OTH) AF: 0.0189 AC: 40 AN: 2112

Alfa AF: 0.00992 Hom.: 158

Bravo AF: 0.0318

ESP6500AA AF: 0.0956 AC: 421

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00880 AC: 1068

Asia WGS AF: 0.00318 AC: 11 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	Colorectal cancer;C0476089:Endometrial carcinoma;C1858380:Colorectal cancer, hereditary nonpolyposis, type 7 (1)
-	-	1	Endometrial carcinoma (1)
-	-	1	MLH3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.6
DANN	Benign	0.28
DEOGEN2	Benign	0.070	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	N
PhyloP100		0.084
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.024
Sift	Benign	0.19	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.053
MVP		0.22
MPC		0.13
ClinPred		0.0031	T
GERP RS		-2.7
Varity_R		0.037
gMVP		0.23
Mutation Taster		=299/1	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

Other links and lift over

dbSNP: rs28756988; hg19: chr14-75514200; COSMIC: COSV104587530; COSMIC: COSV104587530;