14-75015186-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001040108.2(MLH3):c.*1896A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 176,226 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (57 hom., cov: 33)
  • Exomes 𝑓: 0.011 (2 hom.)
• Consequence: MLH3 NM_001040108.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.907

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 14-75015186-T-C is Benign according to our data. Variant chr14-75015186-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 314355.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0191 (2911/152352) while in subpopulation AFR AF= 0.0452 (1881/41582). AF 95% confidence interval is 0.0435. There are 57 homozygotes in gnomad4. There are 1398 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 2906 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.*1896A>G		3_prime_UTR_variant	13/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.*1896A>G		3_prime_UTR_variant	13/13	5	NM_001040108.2	P1
MLH3	ENST00000380968.6	c.*1896A>G		3_prime_UTR_variant	12/12	1

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2906 AN: 152234 Hom.: 57 Cov.: 33

Gnomad AFR AF: 0.0453

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00797

Gnomad OTH AF: 0.0158

GnomAD4 exome AF: 0.0110 AC: 262 AN: 23874 Hom.: 2 Cov.: 0 AF XY: 0.0105 AC XY: 115 AN XY: 10916

Gnomad4 AFR exome AF: 0.0303

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.00131

Gnomad4 EAS exome AF: 0.0114

Gnomad4 SAS exome AF: 0.0485

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00978

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.0191 AC: 2911 AN: 152352 Hom.: 57 Cov.: 33 AF XY: 0.0188 AC XY: 1398 AN XY: 74510

Gnomad4 AFR AF: 0.0452

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.0102

Gnomad4 SAS AF: 0.0412

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00797

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0130 Hom.: 3

Bravo AF: 0.0199

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	8.8
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs28757059; hg19: chr14-75481889;