14-75048990-C-T

Variant names:

• chr14-75048990-C-T
• rs28756980
• NM_001040108.2:c.666G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001040108.2(MLH3):​c.666G>A​(p.Lys222Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,986 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (68 hom., cov: 33)
  • Exomes 𝑓: 0.011 (166 hom.)
• Consequence: MLH3 NM_001040108.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.967
• Publications: 8 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-75048990-C-T is Benign according to our data. Variant chr14-75048990-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 314391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.967 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0502 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	NM_001040108.2	MANE Select	c.666G>A	p.Lys222Lys	synonymous	Exon 2 of 13	NP_001035197.1
	MLH3	NM_014381.3		c.666G>A	p.Lys222Lys	synonymous	Exon 2 of 12	NP_055196.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	ENST00000355774.7	TSL:5 MANE Select	c.666G>A	p.Lys222Lys	synonymous	Exon 2 of 13	ENSP00000348020.2
	MLH3	ENST00000380968.6	TSL:1	c.666G>A	p.Lys222Lys	synonymous	Exon 2 of 12	ENSP00000370355.3
	MLH3	ENST00000930871.1		c.666G>A	p.Lys222Lys	synonymous	Exon 2 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3128 AN: 152168 Hom.: 68 Cov.: 33

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00795

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0133 AC: 3319 AN: 250200 AF XY: 0.0141

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.00727

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0123

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00736

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0109 AC: 15905 AN: 1461700 Hom.: 166 Cov.: 35 AF XY: 0.0115 AC XY: 8356 AN XY: 727122

African (AFR) AF: 0.0522 AC: 1748 AN: 33468

American (AMR) AF: 0.00763 AC: 341 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00295 AC: 77 AN: 26130

East Asian (EAS) AF: 0.0101 AC: 401 AN: 39698

South Asian (SAS) AF: 0.0357 AC: 3073 AN: 86192

European-Finnish (FIN) AF: 0.00154 AC: 82 AN: 53410

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

European-Non Finnish (NFE) AF: 0.00835 AC: 9280 AN: 1111938

Other (OTH) AF: 0.0129 AC: 782 AN: 60392

GnomAD4 genome AF: 0.0206 AC: 3132 AN: 152286 Hom.: 68 Cov.: 33 AF XY: 0.0203 AC XY: 1508 AN XY: 74458

African (AFR) AF: 0.0503 AC: 2091 AN: 41550

American (AMR) AF: 0.0111 AC: 169 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.0102 AC: 53 AN: 5186

South Asian (SAS) AF: 0.0413 AC: 199 AN: 4824

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00795 AC: 541 AN: 68040

Other (OTH) AF: 0.0166 AC: 35 AN: 2114

Alfa AF: 0.0101 Hom.: 24

Bravo AF: 0.0215

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Colorectal cancer, hereditary nonpolyposis, type 7 (3)
-	-	3	not specified (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
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.4
DANN	Benign	0.78
PhyloP100		0.97
Mutation Taster		=297/3	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: rs28756980; hg19: chr14-75515693; COSMIC: COSV104587316;