17-43104122-C-G

Position:

chr17-43104122-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_007294.4(BRCA1):c.441G>C(p.Leu147Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000136 in 1,612,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L147L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 4.25

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:

BRCA1 (HGNC:):

BRCA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.441G>C	p.Leu147Phe	missense_variant, splice_region_variant	6/23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.441G>C	p.Leu147Phe	missense_variant, splice_region_variant	6/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151308

Hom.:

Cov.:

show subpopulations

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:

0.0000443

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250660

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135466

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1460740

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726676

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:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151308

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73856

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000443

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 25, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 04, 2019	The BRCA1 c.441G>C; p.Leu147Phe variant (rs748876625) is reported in the literature in individuals with hereditary breast and ovarian cancer syndrome (Michils 2012, Moghadasi 2013), and reported multiple times in the LOVD BRCA1 database (see link). This variant is also reported in ClinVar (Variation ID: 220023). One functional study suggests the variant is neutral based on its ability to restore growth and cisplatin sensitivity in BRCA-null mouse embryonic stem cells (Bouwman 2013). However, another functional study suggests the variant is deleterious as the variant protein displays decreased E3 ligase activity compared to wild type protein (Starita 2015). This variant is found in the general population with an overall allele frequency of 0.002% (5/281702 alleles) in the Genome Aggregation Database. The leucine at codon 147 is highly conserved and the variant is located in the last nucleotide of the exon. Computational analyses (SIFT, PolyPhen-2, Alamut v.2.11) predict that this variant is deleterious and may alter splicing by weakening the nearby canonical donor splice site. However, based on available information, the significance of this variant is uncertain at this time. REFERENCES Bouwman P et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov. 2013 Oct;3(10):1142-55. Link to LOVD BRCA1 database: https://databases.lovd.nl/shared/variants/BRCA1#object_id=VariantOnTranscript%2CVariantOnGenome&id=BRCA1&order=VariantOnTranscript%2FDNA%2CASC&search_transcriptid=00003478&search_VariantOnTranscript/DNA=c.441G%3EC&page_size=100&page=1 Michils G et al. Molecular analysis of the breast cancer genes BRCA1 and BRCA2 using amplicon-based massive parallel pyrosequencing. J Mol Diagn. 2012 Nov;14(6):623-30. Moghadasi S et al. Variants of uncertain significance in BRCA1 and BRCA2 assessment of in silico analysis and a proposal for communication in genetic counselling. J Med Genet. 2013 Feb;50(2):74-9. Starita LM et al. Massively Parallel Functional Analysis of BRCA1 RING Domain Variants. Genetics. 2015 Jun;200(2):413-22. -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 11, 2024	- -

Hereditary breast ovarian cancer syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2022	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 147 of the BRCA1 protein (p.Leu147Phe). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (rs748876625, gnomAD 0.004%). This missense change has been observed to co-occur in individuals with a different variant in BRCA1 that has been determined to be pathogenic (PMID: 21520333, 23231788), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 220023). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 23867111, 25823446, 32546644). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Uncertain significance, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Dec 19, 2023	. According to the ClinGen ENIGMA BRCA1 v1.0.0 criteria we chose this criterium: BS3 (strong benign): Contradictory functional data regarding splice effect. Protein function not affected ( neutral Bouwman P et al. Cancer Discov, 2013 Oct;3:1142-55) Class 3 -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 16, 2024	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 17, 2023	This missense variant replaces leucine with phenylalanine at codon 147 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). One functional study has shown the mutant protein to exhibit normal function in its ability to complement BRCA1-deficiency in mouse embryonic stem cells (PMID: 23867111), while another study has shown the mutant protein to be defective in E3 ligase activity (PMID: 25823446). In addition to the potential impact on protein function, this variant alters the highly conserved guanine nucleotide at the last nucleotide position of exon 6 and is predicted to adversely impact RNA splicing at the adjacent splice donor site in intron 6 by multiple splicing prediction tools. In a RNA study using blood samples, this variant has been shown to cause the retention of intron 6 (referred to as intron 7 in the article based on the BIC nomenclature) and predicted to result in premature protein truncation (PMID: 30832263). This aberrant transcript accounted for 34% of overall gene expression in the patient sample and was undetectable in control samples. Subsequent RNA studies have reported no significant impact of this variant on RNA splicing (PMID: 31143303; unpublished study described in ClinVar SCV000275598.4). However, details of these RNA studies are not available for review. This variant is rare in the population and has been identified in 5/281702 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has been observed in individuals and/or families suspected of having hereditary breast and ovarian cancer (PMID: 23231788, 30832263; Color internal data), as well as in individuals unaffected with cancer (Color internal data). A large breast cancer case-control meta-analysis has reported the observation of this variant in 5/60466 cases and 3/53461 unaffected controls (OR=1.474, 95% CI: 0.352 to 6.167) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001287). This variant has been observed in a proband in trans with a pathogenic variant in the same gene without clinical presentation of Fanconi anemia (unpublished study described in ClinVar SCV000275598.4). In summary, the functional studies have reported conflicting results regarding the variant impact on protein function and RNA splicing, and the clinical data are insufficient to determine conclusively whether this variant is associated with disease. It cannot be ruled out that this variant may be hypomorphic and present with a reduced risk of autosomal dominant hereditary cancer compared to typical pathogenic BRCA1 variants. However, due to conflicting supporting evidence available at this time, this variant is classified as a Variant of Uncertain Significance. -

BRCA1-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 06, 2024

This missense variant replaces leucine with phenylalanine at codon 147 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). One functional study has shown the mutant protein to exhibit normal function in its ability to complement BRCA1-deficiency in mouse embryonic stem cells (PMID: 23867111), while another study has shown the mutant protein to be defective in E3 ligase activity (PMID: 25823446). In addition to the potential impact on protein function, this variant alters the highly conserved guanine nucleotide at the last nucleotide position of exon 6 and is predicted to adversely impact RNA splicing at the adjacent splice donor site in intron 6 by multiple splicing prediction tools. In a RNA study using blood samples, this variant has been shown to cause the retention of intron 6 (referred to as intron 7 in the article based on the BIC nomenclature) and predicted to result in premature protein truncation (PMID: 30832263). This aberrant transcript accounted for 34% of overall gene expression in the patient sample and was undetectable in control samples. Subsequent RNA studies have reported no significant impact of this variant on RNA splicing (PMID: 31143303; unpublished study described in ClinVar SCV000275598.4). However, details of these RNA studies are not available for review. This variant is rare in the population and has been identified in 5/281702 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has been observed in individuals and/or families suspected of having hereditary breast and ovarian cancer (PMID: 23231788, 30832263; Color internal data), as well as in individuals unaffected with cancer (Color internal data). A large breast cancer case-control meta-analysis has reported the observation of this variant in 5/60466 cases and 3/53461 unaffected controls (OR=1.474, 95% CI: 0.352 to 6.167) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001287). This variant has been observed in a proband in trans with a pathogenic variant in the same gene without clinical presentation of Fanconi anemia (unpublished study described in ClinVar SCV000275598.4). In summary, the functional studies have reported conflicting results regarding the variant impact on protein function and RNA splicing, and the clinical data are insufficient to determine conclusively whether this variant is associated with disease. It cannot be ruled out that this variant may be hypomorphic and present with a reduced risk of autosomal dominant hereditary cancer compared to typical pathogenic BRCA1 variants. However, due to conflicting supporting evidence available at this time, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 20, 2019

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 23231788, 23867111, 23034506, 19370767, 25823446, 31143303, 30832263) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;T;T;D;D;D;D;D;D;D;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.34

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.5

M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.3

N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.0070

D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D

Sift4G

Benign

0.15

T;D;D;T;D;T;.;.;T;.;D;.;D;.;D;.

Polyphen

1.0, 1.0

.;D;.;.;.;D;.;D;.;.;D;.;.;.;.;.

Vest4

0.40

MutPred

0.15

Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);.;.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);

MVP

0.99

MPC

0.44

ClinPred

0.70

GERP RS

5.3

Varity_R

0.19

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.18

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