17-43092169-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_007294.4(BRCA1):c.3362A>G(p.Asn1121Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,344 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. N1121D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:6
• Conservation: PhyloP100: -0.0740

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09063476).
• BP6: Variant 17-43092169-T-C is Benign according to our data. Variant chr17-43092169-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37527.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3362A>G	p.Asn1121Ser	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3362A>G	p.Asn1121Ser	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000160 AC: 4 AN: 250354 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135504

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000579

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461098 Hom.: 0 Cov.: 39 AF XY: 0.00000688 AC XY: 5 AN XY: 726868

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74386

Gnomad4 AFR AF: 0.0000724

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: 0.0000338 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 05, 2015	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	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 26, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 19, 2021	- -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:1

Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 24, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 26, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Nov 25, 2004	- -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 29, 2020	The BRCA1 c.3362A>G; p.Asn1121Ser variant (rs80356919) is reported in the literature in an individual affected with ovarian cancer, but without a clear disease association (Minucci 2015). This variant is reported in ClinVar (Variation ID: 37527), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 1121 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Additionally, a multifactorial likelihood analysis categorized this variant as likely benign (Parsons 2019). However, given the lack of clinical and functional data, the significance of the p.Asn1121Ser variant is uncertain at this time. References: Minucci A et al. Clinical impact on ovarian cancer patients of massive parallel sequencing for BRCA mutation detection: the experience at Gemelli hospital and a literature review. Expert Rev Mol Diagn. 2015;15(10):1383-1403. Parsons MT et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019;40(9):1557-1578. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26306726, 31131967) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 12, 2023	In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 26306726 (2015)). A multifactorial analysis study has reported that this variant is likely not pathogenic (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.000016 (4/250354 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary breast ovarian cancer syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 26, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 03, 2019

Variant summary: BRCA1 c.3362A>G (p.Asn1121Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250354 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3362A>G has been reported in the literature at-least once in an individual affected with sporadic and/or familial Ovarian Cancer (Minucci_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 (VUS, n=3; benign/likely benign, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	0.65
Dann	Benign	0.47
DEOGEN2	Benign	0.33	T;.;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.022	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.091	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Benign	0.24
Sift	Benign	0.41	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.010	B;.;.;B
Vest4		0.28
MVP		0.34
MPC		0.090
ClinPred		0.020	T
GERP RS		-0.24
Varity_R		0.036
gMVP		0.038

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

Other links and lift over

dbSNP: rs80356919; hg19: chr17-41244186;