rs114829239

Variant names:

• chr14-75049648-T-C
• rs114829239
• NM_001040108.2:c.8A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001040108.2(MLH3):​c.8A>G​(p.Lys3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,958 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (23 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (19 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.42
• Publications: 6 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 -16 ACMG points.

• BP6: Variant 14-75049648-T-C is Benign according to our data. Variant chr14-75049648-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00842 (1283/152318) while in subpopulation AFR AF = 0.0283 (1178/41558). AF 95% confidence interval is 0.027. There are 23 homozygotes in GnomAd4. There are 598 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AD,AR gene

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.8A>G	p.Lys3Arg	missense	Exon 2 of 13	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.8A>G	p.Lys3Arg	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.8A>G	p.Lys3Arg	missense	Exon 2 of 13	ENSP00000348020.2	Q9UHC1-1
	MLH3	ENST00000380968.6	TSL:1	c.8A>G	p.Lys3Arg	missense	Exon 2 of 12	ENSP00000370355.3	Q9UHC1-2
	MLH3	ENST00000930871.1		c.8A>G	p.Lys3Arg	missense	Exon 2 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes AF: 0.00842 AC: 1282 AN: 152200 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00228 AC: 571 AN: 250216 AF XY: 0.00171

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000952 AC: 1392 AN: 1461640 Hom.: 19 Cov.: 35 AF XY: 0.000811 AC XY: 590 AN XY: 727100

African (AFR) AF: 0.0285 AC: 955 AN: 33478

American (AMR) AF: 0.00260 AC: 116 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000151 AC: 168 AN: 1111878

Other (OTH) AF: 0.00220 AC: 133 AN: 60390

GnomAD4 genome AF: 0.00842 AC: 1283 AN: 152318 Hom.: 23 Cov.: 33 AF XY: 0.00803 AC XY: 598 AN XY: 74488

African (AFR) AF: 0.0283 AC: 1178 AN: 41558

American (AMR) AF: 0.00438 AC: 67 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68036

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00314 Hom.: 11

Bravo AF: 0.00934

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00272 AC: 330

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.15	N
PhyloP100		1.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.22
Sift	Benign	0.59	T
Sift4G	Benign	0.48	T
Polyphen		0.0080	B
Vest4		0.087
MVP		0.83
MPC		0.085
ClinPred		0.0046	T
GERP RS		3.2
Varity_R		0.041
gMVP		0.29
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: 0

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

Other links and lift over

dbSNP: rs114829239; hg19: chr14-75516351; COSMIC: COSV104587318;