NM_000249.4:c.1039-8_1039-7insTTTTTTTA

Variant names:

• chr3-37025629-T-TTTTTTTTA
• rs535965616
• NM_000249.4:c.1039-8_1039-7insTTTTTTTA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000249.4(MLH1):​c.1039-8_1039-7insTTTTTTTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000030 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000046 (1 hom.)
• Consequence: MLH1 NM_000249.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:5
• Conservation: PhyloP100: 0.0980

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP6: Variant 3-37025629-T-TTTTTTTTA is Benign according to our data. Variant chr3-37025629-T-TTTTTTTTA is described in ClinVar as [Benign]. Clinvar id is 215448.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1039-8_1039-7insTTTTTTTA		splice_region_variant, intron_variant	Intron 11 of 18	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1039-8_1039-7insTTTTTTTA		splice_region_variant, intron_variant	Intron 11 of 18	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes AF: 0.0000296 AC: 4 AN: 135300 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000223

Gnomad FIN AF: 0.000125

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000313

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000462 AC: 51 AN: 1103210 Hom.: 1 Cov.: 20 AF XY: 0.0000367 AC XY: 20 AN XY: 545208

Gnomad4 AFR exome AF: 0.0000474

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000271

Gnomad4 NFE exome AF: 0.0000514

Gnomad4 OTH exome AF: 0.0000685

GnomAD4 genome AF: 0.0000296 AC: 4 AN: 135290 Hom.: 0 Cov.: 19 AF XY: 0.0000459 AC XY: 3 AN XY: 65430

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000224

Gnomad4 FIN AF: 0.000125

Gnomad4 NFE AF: 0.0000313

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000474 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MLH1 c.1039-8_1039-7insTTTTTA variant was not identified in the literature nor was it identified in dbSNP, COSMIC, Mismatch Repair Genes Variant Database, MMR Gene Unclassified Variants Database, InSiGHT Colon Cancer Gene Variant Database, Zhejiang Colon Cancer, COGR, or UMD databases. The variant was identified in the Clinvar database (classified as benign by Invitae). Clinvar also documents multiple variant deletions and insertions in this 5’ polynucleotide stretch as benign or likely benign. The variant was identified in control databases in 3079 of 118408 chromosomes (58 homozygous) at a frequency of 0.03, increasing the likelihood this could be a benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 524 of 5932 chromosomes (freq: 0.09), European (Non-Finnish) in 1791 of 58686 chromosomes (freq: 0.03), Other in 59 of 2174 chromosomes (freq: 0.03), East Asian in 121 of 5950 chromosomes (freq: 0.02), Finnish in 270 of 15534 chromosomes (freq: 0.02), Latino in 111 of 8698 chromosomes (freq: 0.01), South Asian in 157 of 16556 chromosomes (freq: 0.009), and Ashkenazi Jewish in 46 of 4878 chromosomes (freq: 0.009). In a study of Slovenian patients with gastric cancer, the variant IVS12 1039-7delT(n) is considered a germline polymorphism, co-occurring with pathogenic germline MLH1 mutation(s), detected in matched normal and tumour tissue of these patients (Hudler 2004). The variant occurs outside of the splicing consensus sequence and 2 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs535965616; hg19: chr3-37067120;