chr14-75015205-A-G

Position:

• chr14-75015205-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001040108.2(MLH3):​c.*1877T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 176,520 control chromosomes in the GnomAD database, including 14,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (12485 hom., cov: 32)
  • Exomes 𝑓: 0.38 (1966 hom.)
• Consequence: MLH3 NM_001040108.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21

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=-0.55).
• BP6: Variant 14-75015205-A-G is Benign according to our data. Variant chr14-75015205-A-G is described in ClinVar as [Benign]. Clinvar id is 314356.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.*1877T>C		3_prime_UTR_variant	13/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.*1877T>C		3_prime_UTR_variant	13/13	5	NM_001040108.2	P1
MLH3	ENST00000380968.6	c.*1877T>C		3_prime_UTR_variant	12/12	1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60088 AN: 151976 Hom.: 12478 Cov.: 32

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.413

GnomAD4 exome AF: 0.383 AC: 9352 AN: 24426 Hom.: 1966 Cov.: 0 AF XY: 0.382 AC XY: 4253 AN XY: 11134

Gnomad4 AFR exome AF: 0.324

Gnomad4 AMR exome AF: 0.361

Gnomad4 ASJ exome AF: 0.459

Gnomad4 EAS exome AF: 0.162

Gnomad4 SAS exome AF: 0.505

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.453

Gnomad4 OTH exome AF: 0.424

GnomAD4 genome AF: 0.395 AC: 60114 AN: 152094 Hom.: 12485 Cov.: 32 AF XY: 0.395 AC XY: 29330 AN XY: 74340

Gnomad4 AFR AF: 0.313

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.472

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.461

Gnomad4 FIN AF: 0.444

Gnomad4 NFE AF: 0.457

Gnomad4 OTH AF: 0.421

Alfa AF: 0.418 Hom.: 4242

Bravo AF: 0.380

Asia WGS AF: 0.355 AC: 1232 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.61

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: rs108622; hg19: chr14-75481908;