rs28756990

Variant names:

• chr14-75047435-C-A
• rs28756990
• NM_001040108.2:c.2221G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-75047435-C-A
• chr14-75047435-C-G
• chr14-75047435-C-T

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.2221G>T​(p.Val741Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,926 control chromosomes in the GnomAD database, including 235 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V741I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (68 hom., cov: 33)
  • Exomes 𝑓: 0.011 (167 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 B:13
• Conservation: PhyloP100: -0.895
• Publications: 34 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=0.0023878515).
• BP6: Variant 14-75047435-C-A is Benign according to our data. Variant chr14-75047435-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 5561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 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.2221G>T	p.Val741Phe	missense	Exon 2 of 13	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.2221G>T	p.Val741Phe	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.2221G>T	p.Val741Phe	missense	Exon 2 of 13	ENSP00000348020.2	Q9UHC1-1
	MLH3	ENST00000380968.6	TSL:1	c.2221G>T	p.Val741Phe	missense	Exon 2 of 12	ENSP00000370355.3	Q9UHC1-2
	MLH3	ENST00000930871.1		c.2221G>T	p.Val741Phe	missense	Exon 2 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3128 AN: 152084 Hom.: 68 Cov.: 33

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0418

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00794

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0134 AC: 3378 AN: 251380 AF XY: 0.0142

Gnomad AFR exome AF: 0.0478

Gnomad AMR exome AF: 0.00729

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.0122

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00741

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0109 AC: 15960 AN: 1461726 Hom.: 167 Cov.: 35 AF XY: 0.0115 AC XY: 8396 AN XY: 727170

African (AFR) AF: 0.0523 AC: 1752 AN: 33478

American (AMR) AF: 0.00762 AC: 341 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00295 AC: 77 AN: 26132

East Asian (EAS) AF: 0.0101 AC: 402 AN: 39684

South Asian (SAS) AF: 0.0361 AC: 3112 AN: 86254

European-Finnish (FIN) AF: 0.00156 AC: 83 AN: 53376

Middle Eastern (MID) AF: 0.0210 AC: 121 AN: 5768

European-Non Finnish (NFE) AF: 0.00835 AC: 9287 AN: 1111918

Other (OTH) AF: 0.0130 AC: 785 AN: 60392

GnomAD4 genome AF: 0.0206 AC: 3134 AN: 152200 Hom.: 68 Cov.: 33 AF XY: 0.0203 AC XY: 1512 AN XY: 74410

African (AFR) AF: 0.0504 AC: 2091 AN: 41508

American (AMR) AF: 0.0111 AC: 169 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.0102 AC: 53 AN: 5188

South Asian (SAS) AF: 0.0419 AC: 202 AN: 4824

European-Finnish (FIN) AF: 0.00142 AC: 15 AN: 10592

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00794 AC: 540 AN: 68014

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.0121 Hom.: 88

Bravo AF: 0.0215

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.0520 AC: 229

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.0145 AC: 1762

Asia WGS AF: 0.0280 AC: 97 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
1	-	2	Colorectal cancer, hereditary nonpolyposis, type 7 (3)
-	-	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	0.094
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.0
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.90
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.034	D
Sift4G	Uncertain	0.045	D
Polyphen		0.89	P
Vest4		0.12
MPC		0.40
ClinPred		0.037	T
GERP RS		-6.3
Varity_R		0.044
gMVP		0.31
Mutation Taster		=300/0	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: rs28756990; hg19: chr14-75514138; COSMIC: COSV104587511;