17-43070973-G-T

Position:

chr17-43070973-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6

The ENST00000357654.9(BRCA1):c.4941C>A(p.Asn1647Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1647D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA1
ENST00000357654.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4O:1

Conservation

PhyloP100: -0.0550

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 17 uncertain in ENST00000357654.9

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1268673).

BP6

Variant 17-43070973-G-T is Benign according to our data. Variant chr17-43070973-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55325.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.4941C>A	p.Asn1647Lys	missense_variant	15/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 linkuse as main transcript	c.4941C>A	p.Asn1647Lys	missense_variant	15/23	1	NM_007294.4	ENSP00000350283	P4	P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Other:1

not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 30, 1998	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 10, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 18, 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 2014

This variant is denoted BRCA1 c.4941C>A at the cDNA level, p.Asn1647Lys (N1647K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAA). This variant was found in one study to have no protein folding defect, normal peptide binding activity and specificity, and normal trascriptional activity (Lee 2010). BRCA1 Asn1647Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative substitution in which a neutral polar amino acid is replaced with a positive polar one, altering a position that is only moderately conserved throughout evolution and is located in BRCT1 domain (UniProt). In silico analyses predict this variant to have a benign effect on protein structure and function. Based on the currently available information, we consider BRCA1 Asn1647Lys to be a variant of uncertain significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Oct 27, 2022

Variant summary: BRCA1 c.4941C>A (p.Asn1647Lys) results in a non-conservative amino acid change located in the BRCT domain superfamily of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251200 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4941C>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. Three independent functional studies reported the variant to have no protein folding defect, normal peptide binding activity and specificity, normal transcriptional activity (example, Lee_2010, Wood_2016), and functional HDR activity (example, Findlay_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Benign

6.3

DANN

Benign

0.41

DEOGEN2

Benign

0.10

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.77

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

M_CAP

Benign

0.063

MetaRNN

Benign

0.13

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

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.49

.;N;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.5

N;N;.;N;.;N;N;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.44

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

Sift4G

Benign

0.94

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

Polyphen

0.0, 0.0010

.;B;.;.;.;.;.;.;B;.

Vest4

0.27

MVP

0.55

MPC

0.098

ClinPred

0.029

GERP RS

-0.72

Varity_R

0.25

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

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