rs587779886

Variant names:

• chr15-90794358-GT-G
• rs587779886
• NM_000057.4:c.3210+2delT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000057.4(BLM):​c.3210+2delT variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000318 in 1,572,194 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: BLM NM_000057.4 splice_donor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.60
• Publications: 3 publications found

Genes affected

BLM (HGNC:1058): (BLM RecQ like helicase) The Bloom syndrome is an autosomal recessive disorder characterized by growth deficiency, microcephaly and immunodeficiency among others. It is caused by homozygous or compound heterozygous mutation in the gene encoding DNA helicase RecQ protein on chromosome 15q26. This Bloom-associated helicase unwinds a variety of DNA substrates including Holliday junction, and is involved in several pathways contributing to the maintenance of genome stability. Identification of pathogenic Bloom variants is required for heterozygote testing in at-risk families. [provided by RefSeq, May 2020]

BLM Gene-Disease associations (from GenCC):

• Bloom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet, Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ENSG00000300894 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.1, offset of -47, new splice context is: tttGTaaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 15-90794358-GT-G is Pathogenic according to our data. Variant chr15-90794358-GT-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 127497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000057.4. 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
	BLM	NM_000057.4	MANE Select	c.3210+2delT		splice_donor intron	N/A	NP_000048.1
	BLM	NM_001287246.2		c.3210+2delT		splice_donor intron	N/A	NP_001274175.1
	BLM	NM_001287247.2		c.3210+2delT		splice_donor intron	N/A	NP_001274176.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.3210+2delT		splice_donor intron	N/A	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.3210+2delT		splice_donor intron	N/A	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.*2134+2delT		splice_donor intron	N/A	ENSP00000453359.1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151674 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000463 AC: 1 AN: 216206 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000100

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000324 AC: 46 AN: 1420520 Hom.: 0 Cov.: 30 AF XY: 0.0000255 AC XY: 18 AN XY: 705470

African (AFR) AF: 0.0000634 AC: 2 AN: 31538

American (AMR) AF: 0.00 AC: 0 AN: 37816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24992

East Asian (EAS) AF: 0.00 AC: 0 AN: 38858

South Asian (SAS) AF: 0.00 AC: 0 AN: 77146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5076

European-Non Finnish (NFE) AF: 0.0000384 AC: 42 AN: 1094368

Other (OTH) AF: 0.0000342 AC: 2 AN: 58518

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151674 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74078

African (AFR) AF: 0.00 AC: 0 AN: 41256

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Pathogenic:7

Nov 04, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a splice site in intron 16 of the BLM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs587779886, gnomAD 0.001%). Disruption of this splice site has been observed in individual(s) with mesothelioma (PMID: 26556299, 29439820). ClinVar contains an entry for this variant (Variation ID: 127497). Studies have shown that disruption of this splice site results in skipping of exon 16, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.

Aug 16, 2017

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 13, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BLM c.3210+2del intronic change results in the deletion of one nucleotide in intron 16 of the BLM gene. This variant is predicted to result in loss of the native splice donor site and abnormal gene splicing, resulting in nonsense-mediated decay or an abnormal protein product. This variant has been reported in at least one individual with metastatic prostate cancer (PMID: 29439820, 31816118) and in individuals with mesothelioma (PMID: 26556299). It has a maximum subpopulation frequency of 0.0010% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). To our knowledge, this variant has not been reported in individuals with Bloom syndrome. In summary, this variant meets criteria to be classified as likely pathogenic.

Jan 20, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BLM c.3210+2delT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.6e-06 in 216206 control chromosomes (gnomAD). c.3210+2delT has been reported in the literature in individuals affected with prostate cancer (Antonarakis_2018, Ledet_2020) and mesothelioma (Schrader _2016). In these individuals, a second pathogenic variant has not been reported. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other ClinVar submitters (evaluation after 2014) classify the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Jan 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 15, 2025

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Apr 04, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BLM c.3210+2del variant disrupts a canonical splice-donor site and is predicted to interfere with normal BLM mRNA splicing. This variant has been reported in the published literature in individuals with breast cancer (PMID: 36315097 (2022)), prostate cancer (PMIDs: 31816118 (2020), 29439820 (2018)), leukemia (PMID: 31604778 (2019)), and mesothelioma (PMID: 26556299 (2016)). However, this variant in the heterozygous state has also been observed in several reportedly healthy young/middle-age individuals (PMID: 32906206 (2020), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.0000046 (1/216206 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as likely pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 17, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3210+2delT intronic variant is located 2 nucleotides after coding exon 15 of the BLM gene. This variant results from a deletion of one nucleotide at position c.3210+2. This variant has been detected in metastatic prostate cancer patients (Antonarakis ES et al. Eur Urol. 2018 Aug;74(2):218-225; Ledet EM et al. Prostate, 2020 02;80:235-237). This variant has also been observed in individuals affected with mesothelioma (Schrader KA et al. JAMA Oncol, 2016 Jan;2:104-11). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.48		Position offset: -48
DS_DL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs587779886; hg19: chr15-91337588;