rs371973519

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_007294.4(BRCA1):c.441+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000769 in 1,561,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -1.76

Publications

1 publications found

Variant links:

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia, complementation group S
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
pancreatic cancer, susceptibility to, 4
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 17-43104104-G-A is Benign according to our data. Variant chr17-43104104-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.441+18C>T		intron_variant	Intron 6 of 22	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.441+18C>T		intron_variant	Intron 6 of 22	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.000117

AC:

AN:

144688

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000503

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000349

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000227

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000138

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000700

AC:

AN:

228658

AF XY:

0.0000645

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000514

Gnomad NFE exome

AF:

0.0000939

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000727

AC:

103

AN:

1416356

Hom.:

Cov.:

AF XY:

0.0000736

AC XY:

AN XY:

706172

show subpopulations

African (AFR)

AF:

0.0000307

AC:

AN:

32572

American (AMR)

AF:

0.000115

AC:

AN:

43558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25594

East Asian (EAS)

AF:

0.00

AC:

AN:

39184

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83470

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52222

Middle Eastern (MID)

AF:

0.000358

AC:

AN:

5582

European-Non Finnish (NFE)

AF:

0.0000790

AC:

AN:

1075532

Other (OTH)

AF:

0.000136

AC:

AN:

58642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

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:

0.000117

AC:

AN:

144790

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

70496

show subpopulations

African (AFR)

AF:

0.0000501

AC:

AN:

39908

American (AMR)

AF:

0.000348

AC:

AN:

14352

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3346

East Asian (EAS)

AF:

0.00

AC:

AN:

4864

South Asian (SAS)

AF:

0.000228

AC:

AN:

4394

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000138

AC:

AN:

65208

Other (OTH)

AF:

0.00

AC:

AN:

2018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.543

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:

0.000142

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Sep 23, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA1 c.441+18C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 2/2 computational tools predict no significant impact on normal splicing, and these predictions were confirmed by an mRNA transcript analysis (Houdayer 2012). The variant allele was found at a frequency of 8.1e-05 in 258156 control chromosomes (gnomAD). This frequency is not higher than the expected maximum for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (8.1e-05 vs 0.001), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.441+18C>T in individuals affected with Hereditary Breast and Ovarian Cancer has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (1x) / likely benign (3x). Based on the evidence outlined above, the variant was classified as benign. -

Jul 24, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 1

Benign:4

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Likely benign

Review Status:criteria provided, single submitter

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

- -

Jul 28, 2016

Counsyl

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 27, 2017

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Jun 23, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 20, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1_Supporting, BP4, BP7 c.441+18C>T is an intronic variant not very close to a canonical splice site, where the SpliceAI algorithm predicts no significant impact on splicing (BP4, BP7). The variant allele was found in 14/110112 alleles, with a filter allele frequency of 0.0062% at 99% confidence, within the European (non-Finnish) population in the gnomAD v2.1.1 database (non-cancer data set) (BS1_Supporting). To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. In addition, it was also identified in the following databases: BRCA Exchange (Not Yet Reviewed), ClinVar (5x benign, 8x likely benign) and LOVD (2x benign, 4x likely benign, 5x uncertain significance, 1x pathogenic). Based on the currently available information, c.441+18C>T is classified as a likely benign variant according to ClinGen-BRCA1 Guidelines version v1.0.0. -

Hereditary breast ovarian cancer syndrome

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.39

(source)

DANN

Benign

0.54

PhyloP100

-1.8

Mutation Taster

=100/0

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