17-43104167-G-T

Position:

chr17-43104167-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_007294.4(BRCA1):c.396C>A(p.Asn132Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:18

Conservation

PhyloP100: 1.17

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 Benign. Variant got -8 ACMG points.

BP6

Variant 17-43104167-G-T is Benign according to our data. Variant chr17-43104167-G-T is described in ClinVar as [Benign]. Clinvar id is 55064.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43104167-G-T is described in Lovd as [Benign]. Variant chr17-43104167-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.396C>A	p.Asn132Lys	missense_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.396C>A	p.Asn132Lys	missense_variant	6/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152144

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251426

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135888

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:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000486

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74332

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000501

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 09, 2022	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 2/66738 European chromosomes; ClinVar: 3 labs B/LB, 1 lab VUS; at least 3 papers describe as non pathogenic -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:6

Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000166 -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 13, 2009	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2017	Variant summary: The BRCA1 c.396C>A (p.Asn132Lys) variant (alternatively also known as 515C>A) involves the alteration of a non-conserved nucleotide and is not located in a known functional domain, while 4/5 in silico tools predict a damaging outcome for this variant. However, multiple functional studies demonstrated that this variant does not affect BRCA1 function (Towler_2013, Caligo_2009, Bouwman_2013, Maresca_2015, Thouvenot_2016). This variant was found in 2/121408 control chromosomes from ExAC at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in several HBOC patients without clear evidence supporting causality. The variant of interest was found to co-occur with another pathogenic BRCA2 variant, c.4936_4939delGAAA (p.Glu1646fxX23 - classified as pathogenic by LCA) has been reported, supporting a benign outcome. Multifactorial probability based model integrating multiple forms of genetic evidence indicates that the variant is benign (Lindor_2012 and Easton_2007). In addition, multiple clinical diagnostic laboratories/reputable databases/publications classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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	Jun 06, 2016	- -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Asn132Lys variant was identified in 1 of 552 proband chromosomes (frequency: 0.002) from Italian families with breast and ovarian cancer; and, functional assay(s) utilizing yeast based systems were discrepant; the variant was suggested to be neutral as it mapped outside the C-terminus domain; however, it was categorized as potentially deleterious, based on a significant induction of recombination in a yeast â€šÃ„Ã¬ HR (homologous recombination) based assay (Caligo 2008). In another functional assay measuring cell proliferation as an indicator of ability of the variant to compliment BRCA1 deficient mouse embryonic stem cells, the p.Asn132Lys variant was assessed to be neutral (Bouwman 2013). A third functional assay using HDR (homology directed recombination) to assess the 2 pathways of DNA repair BRCA1 is involved in: (DSB-double strand DNA breaks, and SSA â€šÃ„Ã¬ single strand annealing) showed that the variant had wildtype function in both assays, making it nonpathogenic (Towler 2013). Further, in a predictive posterior probability model that uses several sources of information to classify VUS, the variant was concluded to be nonpathogenic (Lindor 2012). The variant was identified in dbSNP (ID: rs80357413) â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined The variant was also identified in dbSNP (ID: rs80357413s) â€šÃ„ÃºWith likely benign alleleâ€šÃ„Ã¹, Clinvitae database (2X as â€šÃ„Ãºbenignâ€šÃ„Ã¹ and 1X as â€šÃ„Ãºlikely benignâ€šÃ„Ã¹), Fanconi Anemia Mutation Database (LOVD), ARUP Laboratories BRCA Mutations Database (as no clinical significance), the ClinVar database (classified as â€šÃ„Ãºbenignâ€šÃ„Ã¹), the BIC database (5X with unknown clinical importance), and UMD (4X with a â€šÃ„Ãºlikely neutralâ€šÃ„Ã¹ classification), Fanconi Anemia Mutation Database (LOVD) as likely neutral). The variant was also identified by the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 2 of 66738 (European (Non-Finnish)) alleles (frequency: 2.997E-05), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Asn132residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; however, this information 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

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

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.50

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

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.5

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

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.2

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

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0040

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

Sift4G

Benign

0.28

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

Polyphen

0.84, 1.0, 1.0, 0.99

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

Vest4

0.55

MutPred

0.73

Gain of methylation at N132 (P = 0.0115);Gain of methylation at N132 (P = 0.0115);Gain of methylation at N132 (P = 0.0115);Gain of methylation at N132 (P = 0.0115);.;Gain of methylation at N132 (P = 0.0115);.;Gain of methylation at N132 (P = 0.0115);.;.;Gain of methylation at N132 (P = 0.0115);Gain of methylation at N132 (P = 0.0115);Gain of methylation at N132 (P = 0.0115);.;Gain of methylation at N132 (P = 0.0115);Gain of methylation at N132 (P = 0.0115);

MVP

0.91

MPC

0.13

ClinPred

0.22

GERP RS

2.3

Varity_R

0.23

gMVP

0.39

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

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