rs55725216

Variant names:

• chr14-75048019-C-A
• rs55725216
• NM_001040108.2:c.1637G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-75048019-C-A
• chr14-75048019-C-T
• chr14-75048019-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001040108.2(MLH3):​c.1637G>T​(p.Arg546Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,613,594 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R546G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (5 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.0540
• 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047210157).
• BP6: Variant 14-75048019-C-A is Benign according to our data. Variant chr14-75048019-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238244.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000486 (74/152288) while in subpopulation SAS AF = 0.00476 (23/4830). AF 95% confidence interval is 0.00325. There are 1 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.1637G>T	p.Arg546Ile	missense	Exon 2 of 13	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.1637G>T	p.Arg546Ile	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.1637G>T	p.Arg546Ile	missense	Exon 2 of 13	ENSP00000348020.2	Q9UHC1-1
	MLH3	ENST00000380968.6	TSL:1	c.1637G>T	p.Arg546Ile	missense	Exon 2 of 12	ENSP00000370355.3	Q9UHC1-2
	MLH3	ENST00000930871.1		c.1637G>T	p.Arg546Ile	missense	Exon 2 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152170 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000767 AC: 192 AN: 250382 AF XY: 0.000945

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000564

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.000521 AC: 761 AN: 1461306 Hom.: 5 Cov.: 35 AF XY: 0.000644 AC XY: 468 AN XY: 726904

African (AFR) AF: 0.000120 AC: 4 AN: 33452

American (AMR) AF: 0.000336 AC: 15 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00401 AC: 345 AN: 86020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.000289 AC: 321 AN: 1111878

Other (OTH) AF: 0.000944 AC: 57 AN: 60372

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152288 Hom.: 1 Cov.: 33 AF XY: 0.000618 AC XY: 46 AN XY: 74464

African (AFR) AF: 0.000217 AC: 9 AN: 41562

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

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

South Asian (SAS) AF: 0.00476 AC: 23 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000622 Hom.: 0

Bravo AF: 0.000366

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000799 AC: 97

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Colorectal cancer, hereditary nonpolyposis, type 7 (2)
-	1	1	not specified (2)
-	-	1	Colorectal cancer;C0476089:Endometrial carcinoma;C1858380:Colorectal cancer, hereditary nonpolyposis, type 7 (1)
-	-	1	Endometrial carcinoma (1)
-	-	1	MLH3-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.0
DANN	Benign	0.82
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.054
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.049
Sift	Benign	0.20	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.43
MPC		0.18
ClinPred		0.0077	T
GERP RS		-3.0
Varity_R		0.035
gMVP		0.34
Mutation Taster		=300/0	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: rs55725216; hg19: chr14-75514722;