rs28756986

Variant names:

• chr14-75047786-C-G
• rs28756986
• NM_001040108.2:c.1870G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001040108.2(MLH3):​c.1870G>C​(p.Glu624Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00964 in 1,614,018 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0099 (89 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 1.23
• Publications: 24 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=0.0042276084).
• BP6: Variant 14-75047786-C-G is Benign according to our data. Variant chr14-75047786-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 5560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00745 (1135/152320) while in subpopulation NFE AF = 0.0121 (823/68032). AF 95% confidence interval is 0.0114. There are 6 homozygotes in GnomAd4. There are 528 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.1870G>C	p.Glu624Gln	missense	Exon 2 of 13	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.1870G>C	p.Glu624Gln	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.1870G>C	p.Glu624Gln	missense	Exon 2 of 13	ENSP00000348020.2	Q9UHC1-1
	MLH3	ENST00000380968.6	TSL:1	c.1870G>C	p.Glu624Gln	missense	Exon 2 of 12	ENSP00000370355.3	Q9UHC1-2
	MLH3	ENST00000930871.1		c.1870G>C	p.Glu624Gln	missense	Exon 2 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes AF: 0.00745 AC: 1134 AN: 152202 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00716 AC: 1799 AN: 251246 AF XY: 0.00712

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.00582

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00804

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00987 AC: 14420 AN: 1461698 Hom.: 89 Cov.: 35 AF XY: 0.00959 AC XY: 6976 AN XY: 727156

African (AFR) AF: 0.00185 AC: 62 AN: 33478

American (AMR) AF: 0.00575 AC: 257 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00394 AC: 103 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00167 AC: 144 AN: 86198

European-Finnish (FIN) AF: 0.00953 AC: 509 AN: 53418

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

European-Non Finnish (NFE) AF: 0.0115 AC: 12792 AN: 1111914

Other (OTH) AF: 0.00894 AC: 540 AN: 60386

GnomAD4 genome AF: 0.00745 AC: 1135 AN: 152320 Hom.: 6 Cov.: 33 AF XY: 0.00709 AC XY: 528 AN XY: 74492

African (AFR) AF: 0.00221 AC: 92 AN: 41568

American (AMR) AF: 0.00771 AC: 118 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

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

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00641 AC: 68 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 823 AN: 68032

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.0109 Hom.: 9

Bravo AF: 0.00689

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.00728 AC: 884

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0100

EpiControl AF: 0.00931

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	3	Colorectal cancer, hereditary nonpolyposis, type 7 (4)
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Benign	0.043	D
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.11
MVP		0.64
MPC		0.11
ClinPred		0.014	T
GERP RS		3.9
Varity_R		0.17
gMVP		0.38
Mutation Taster		=293/7	polymorphism

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: rs28756986; hg19: chr14-75514489; COSMIC: COSV53156471; COSMIC: COSV53156471;