17-43067614-T-G

Position:

chr17-43067614-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6

The NM_007294.4(BRCA1):c.5068A>C(p.Lys1690Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,610,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:5O:1

Conservation

PhyloP100: 4.79

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 1 ACMG points.

PM1

In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4

BP6

Variant 17-43067614-T-G is Benign according to our data. Variant chr17-43067614-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55370.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=8, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.5068A>C	p.Lys1690Gln	missense_variant	16/23	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.5068A>C	p.Lys1690Gln	missense_variant	16/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152188

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:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251360

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1457970

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725550

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000454

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 15, 2019	The BRCA1 c.5068A>C; p.Lys1690Gln variant (rs397507239) variant is published in the medical literature in individuals with breast cancer (Ang 2007, Seo 2004, Li 2017). However, the variant has also been shown to functionally replace the wild type protein in a haploid cell culture model, indicating it is not deleterious (Findlay 2018). The variant is reported as a variant of uncertain significance by several sources and as likely benign by one source in the ClinVar database (Variation ID: 55370) and with an overall allele frequency of 0.003% (9/282724 alleles) in the Genome Aggregation Database. The lysine at this position is conserved but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the variant is uncertain at this time. References: Ang P et al. BRCA1 and BRCA2 mutations in an Asian clinic-based population detected using a comprehensive strategy. Cancer Epidemiol Biomarkers Prev. 2007 Nov;16(11):2276-84. Findlay GM et al. Accurate classification of BRCA1 variants with saturation genome editing. Nature. 2018 Oct;562(7726):217-222. Li G et al. Analysis of BRCA1/2 mutation spectrum and prevalence in unselected Chinese breast cancer patients by next-generation sequencing. J Cancer Res Clin Oncol. 2017 Oct;143(10):2011-2024. Seo JH et al. BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer. Hum Mutat. 2004 Oct;24(4):350. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2021	Variant summary: BRCA1 c.5068A>C (p.Lys1690Gln) results in a conservative amino acid change located in the BRCT domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Cline_2019). The variant allele was found at a frequency of 3.2e-05 in 251460 control chromosomes, predominantly at a frequency of 0.00044 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5068A>C, has been reported in the literature in individuals affected with breast and/or ovarian Cancer, predominantly of Asian origin (example, Ang_2007, Lang_2017, Li_2017, Lu_2015, Park_2017, Ryu_2017, Seo_2004, Wong_2016, Zhong_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been reported (BRCA2 c.9294C>G, p.Y3098X, Wong_2016), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on homology directed repair (example, Findlay_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=6). At-least two submitters have re-classified this variant as likely benign since its previous evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 05, 2019	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 07, 2021	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 18, 2023	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 15365993 (2004), 18006916 (2007), 29263802 (2016), 30287823 (2018), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1), breast and/or ovarian cancer (PMID: 28364669 (2017), 35205313 (2022)), and in unaffected individuals (PMID: 30287823 (2018), 32467295 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1)). The effect of this variant on protein function is conflicting. Two functional studies reported this variant was functionally normal in a homology-directed DNA repair assay (PMID: 26689913 (2015)), and a saturation genome editing assay (PMID: 30209399 (2018)). However, another functional study reported this variant was defective in homology-directed DNA repair and was mostly insoluble in an E.coli solubility assay (PMID: 30257991 (2018)). The frequency of this variant in the general population, 0.00045 (9/19948 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2023	Published functional studies are inconclusive: conflicting homology-directed repair ability, defective protein instability, but normal nuclear localization and classified as functional by a saturation genome editing survival assay (PMID: 26689913, 30209399, 30257991); Observed in multiple individuals with breast or other cancers (PMID: 15365993, 18006916, 26221963, 28111427, 28364669, 31825140, 35205313); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5187A>C; This variant is associated with the following publications: (PMID: 24772314, 28111427, 15365993, 26689913, 28664449, 28364669, 18006916, 21147198, 27257965, 26221963, 22333603, 30257991, 30209399, 30702160, 31470354, 31825140, 32467295, 33087888, 32803532, 29263802, 35205313, 36243179, 34621001, 31131967, 25348405) -

Hereditary breast ovarian cancer syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Breast Center, Key Laboratory of Carcinogenesis and Translational Research	May 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Breast-ovarian cancer, familial, susceptibility to, 1

Benign:1Other:1

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Sep 18, 2012	- -

Breast neoplasm

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Nov 01, 2015

- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA1 p.Lys1690Gln variant was identified in 11 of 23576 proband chromosomes (frequency: 0.0005) from Asian individuals or families with breast and/or ovarian cancer and was present in 12 of 22482 control chromosomes (frequency: 0.0005) from healthy individuals (Momozawa 2018, Bhaskaran 2019, Ang 2007). The variant was also identified in dbSNP (ID: rs397507239) as "With Pathogenic, Uncertain significance allele", however it is noted that there is an alternate variant resulting in a stop codon at this position to which the pathogenic classification likely refers, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Color, Invitae and 3 other submitters; and as likely benign by SCRP), LOVD 3.0 (4 entries), UMD-LSDB (1 entry). The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 8 of 277098 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 8 of 18864 chromosomes (freq: 0.0004), while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. In a homology-directed repair assay this variant was shown to have activity comparable to wild type, though insufficient data was available to determine if the finding was statistically significant (Lu 2015). Protein sequence analysis suggests that Lys1690 plays a role in conjugation with small ubiquitin-like modifiers (SUMO) within the BRCT domain though the authors acknowledge that the exact site of conjugation remains unclear (Vialter 2011). The p.Lys1690 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

0.0026

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

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

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Uncertain

0.64

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.6

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

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.6

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

REVEL

Pathogenic

0.72

Sift

Uncertain

0.025

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

Sift4G

Benign

0.090

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

Polyphen

0.73, 1.0

.;P;.;.;.;.;.;.;D;.

Vest4

0.76

MVP

0.92

MPC

0.11

ClinPred

0.39

GERP RS

4.2

Varity_R

0.82

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

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