rs202042636

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000057.4(BLM):c.842A>C(p.His281Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,613,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H281R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9O:1

Conservation

PhyloP100: -0.854

Publications

4 publications found

Variant links:

COSMIC-nc: COSV61927693

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

BLM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.079193115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLM	NM_000057.4 link	c.842A>C	p.His281Pro	missense_variant	Exon 4 of 22	ENST00000355112.8	NP_000048.1	P54132

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8 link	c.842A>C	p.His281Pro	missense_variant	Exon 4 of 22	1	NM_000057.4	ENSP00000347232.3		P54132

Frequencies

GnomAD3 genomes

AF:

0.000144

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000103

AC:

AN:

251246

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000184

AC:

269

AN:

1460846

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

134

AN XY:

726800

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.000179

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000218

AC:

242

AN:

1111214

Other (OTH)

AF:

0.000298

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000144

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41470

American (AMR)

AF:

0.000458

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68046

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000177

Hom.:

Bravo

AF:

0.000170

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bloom syndrome

Uncertain:4

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 281 of the BLM protein (p.His281Pro). This variant is present in population databases (rs202042636, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 127517). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BLM protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:2

Feb 28, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in healthy individuals undergoing whole genome sequencing (Bodian et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327) -

Apr 19, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BLM c.842A>C (p.His281Pro) variant has been reported in the published literature in families at high risk for breast and ovarian cancer (PMIDs: 27153395 (2016) and 30306255 (2018)) as well as in a reportedly healthy individual (PMID: 24728327 (2014)). The frequency of this variant in the general population, 0.0002 (7/35430 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1Other:1

Jun 05, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BLM c.842A>C (p.His281Pro) results in a non-conservative amino acid change located in the RecQ-like DNA helicase BLM, N-terminal domain (IPR032437) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251246 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BLM causing Bloom Syndrome (0.0001 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, c.842A>C has not been reported in the literature in individuals affected with Bloom Syndrome and no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24728327). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

BLM-related disorder

Uncertain:1

Nov 11, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BLM c.842A>C variant is predicted to result in the amino acid substitution p.His281Pro. To variant has been documented in a healthy and ancestrally diverse cohort (Table S1, Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-91295059-A-C) and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127517). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jan 31, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.H281P variant (also known as c.842A>C), located in coding exon 3 of the BLM gene, results from an A to C substitution at nucleotide position 842. The histidine at codon 281 is replaced by proline, an amino acid with similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE, 2014 Apr;9:e94554). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.54

CADD

Benign

2.1

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.45

T;T

M_CAP

Benign

0.0056

MetaRNN

Benign

0.079

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

-0.85

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.025

Sift

Benign

0.046

D;D

Sift4G

Benign

0.28

T;T

Polyphen

0.0010

B;.

Vest4

0.12

MVP

0.75

MPC

0.20

ClinPred

0.023

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.4

Varity_R

0.080

gMVP

0.13

Mutation Taster

=94/6

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over