14-75017109-T-C

Variant names:

• chr14-75017109-T-C
• rs13712
• NM_001040108.2:c.4335A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001040108.2(MLH3):​c.4335A>G​(p.Gln1445Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 1,612,868 control chromosomes in the GnomAD database, including 236,314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21708 hom., cov: 33)
  • Exomes 𝑓: 0.54 (214606 hom.)
• Consequence: MLH3 NM_001040108.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.637
• Publications: 55 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.004).
• BP6: Variant 14-75017109-T-C is Benign according to our data. Variant chr14-75017109-T-C is described in ClinVar as Benign. ClinVar VariationId is 257253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.637 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.816 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.4335A>G	p.Gln1445Gln	synonymous	Exon 13 of 13	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.4263A>G	p.Gln1421Gln	synonymous	Exon 12 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.4335A>G	p.Gln1445Gln	synonymous	Exon 13 of 13	ENSP00000348020.2	Q9UHC1-1
	MLH3	ENST00000380968.6	TSL:1	c.4263A>G	p.Gln1421Gln	synonymous	Exon 12 of 12	ENSP00000370355.3	Q9UHC1-2
	MLH3	ENST00000930871.1		c.4335A>G	p.Gln1445Gln	synonymous	Exon 13 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79996 AN: 152034 Hom.: 21692 Cov.: 33

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.627

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.836

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.523

GnomAD2 exomes AF: 0.575 AC: 144593 AN: 251482 AF XY: 0.564

Gnomad AFR exome AF: 0.443

Gnomad AMR exome AF: 0.749

Gnomad ASJ exome AF: 0.515

Gnomad EAS exome AF: 0.833

Gnomad FIN exome AF: 0.545

Gnomad NFE exome AF: 0.532

Gnomad OTH exome AF: 0.549

GnomAD4 exome AF: 0.537 AC: 784611 AN: 1460716 Hom.: 214606 Cov.: 39 AF XY: 0.535 AC XY: 389080 AN XY: 726696

African (AFR) AF: 0.433 AC: 14492 AN: 33450

American (AMR) AF: 0.734 AC: 32839 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 13352 AN: 26104

East Asian (EAS) AF: 0.828 AC: 32849 AN: 39686

South Asian (SAS) AF: 0.498 AC: 42979 AN: 86238

European-Finnish (FIN) AF: 0.542 AC: 28945 AN: 53362

Middle Eastern (MID) AF: 0.484 AC: 2789 AN: 5766

European-Non Finnish (NFE) AF: 0.526 AC: 584025 AN: 1111046

Other (OTH) AF: 0.536 AC: 32341 AN: 60348

GnomAD4 genome AF: 0.526 AC: 80052 AN: 152152 Hom.: 21708 Cov.: 33 AF XY: 0.529 AC XY: 39380 AN XY: 74386

African (AFR) AF: 0.443 AC: 18378 AN: 41532

American (AMR) AF: 0.627 AC: 9589 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1768 AN: 3468

East Asian (EAS) AF: 0.837 AC: 4333 AN: 5178

South Asian (SAS) AF: 0.495 AC: 2389 AN: 4824

European-Finnish (FIN) AF: 0.554 AC: 5862 AN: 10580

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.530 AC: 36049 AN: 67972

Other (OTH) AF: 0.516 AC: 1090 AN: 2112

Alfa AF: 0.529 Hom.: 32691

Bravo AF: 0.532

Asia WGS AF: 0.603 AC: 2099 AN: 3478

EpiCase AF: 0.532

EpiControl AF: 0.535

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
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.59
PhyloP100		-0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs13712; hg19: chr14-75483812; COSMIC: COSV104996941; COSMIC: COSV104996941;