rs397507234

chr17-43074529-G-Achr17-43074529-G-Cchr17-43074529-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_007294.4(BRCA1):c.4485-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,611,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00007067

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 0.313

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 17-43074529-G-A is Benign according to our data. Variant chr17-43074529-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37599.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3, Benign=1}. Variant chr17-43074529-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.4485-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.4485-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_007294.4	P4	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250888

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135620

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000754

AC:

110

AN:

1459614

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

726250

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.0000982

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 21, 2023	The frequency of this variant in the general population, 0.0000071 (2/282280 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in one family from a cohort of 146 high-risk families with BRCA1 and BRCA2 variants (PMID: 22476429 (2012)). A functional study of breast cancer tumors has reported the variant has an uncertain impact on protein function, however further studies are required to determine the global impact of this variant on BRCA1 protein function (PMID: 26727311 (2015)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect BRCA1 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 c.4485-8C>T variant was identified in 1 of 300 proband chromosomes (frequency: 0.003) from individuals or families with breast cancer (Flower 2015). The variant was also identified in the following databases: dbSNP (ID: rs397507234) as "With other allele", ClinVar (2x uncertain significance, 3x likely benign), Clinvitae, Cosmic (1x, confirmed somatic, in carcinoma of the ovary), and LOVD 3.0 (1x). The variant was classified as a likely benign variant by the Sharing Clinical Reports Project (SCRP, derived from Myriad reports). The variant was not identified in the following databases: COGR, MutDB, UMD-LSDB, BIC Database, ARUP Laboratories, or the Zhejiang University Database. The variant was identified in control databases in 2 of 276702 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). It was observed in the European population in 2 of 126368 chromosomes (freq: 0.00002); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. This variant was classified as â€šÃ„Ãºlikely non-pathogenic or of little clinical significanceâ€šÃ„Ã¹ based on the methylation profile in a breast tumour sample (Flower 2015). The c.4485-8C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 29, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 12, 2011	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 17, 2021

Variant summary: BRCA1 c.4485-8C>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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250888 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4485-8C>T has been reported in the literature in affected individuals without strong evidence for or against pathogenicity (Lu_2012, Flower_2015 ). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two classified as likely benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 09, 2017

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

Cadd

Benign

7.7

Dann

Benign

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000071

dbscSNV1_RF

Benign

0.012

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over