rs80357201

chr17-43092235-G-Achr17-43092235-G-Cchr17-43092235-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):c.3296C>T(p.Pro1099Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,613,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1099R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:26
• Conservation: PhyloP100: 2.53

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14682075).
• BP6: Variant 17-43092235-G-A is Benign according to our data. Variant chr17-43092235-G-A is described in ClinVar as [Benign]. Clinvar id is 41816.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092235-G-A is described in Lovd as [Benign]. Variant chr17-43092235-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.3296C>T	p.Pro1099Leu	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.3296C>T	p.Pro1099Leu	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000303 AC: 76 AN: 250562 Hom.: 0 AF XY: 0.000340 AC XY: 46 AN XY: 135434

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.000469

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000272 AC: 398 AN: 1461326 Hom.: 0 Cov.: 39 AF XY: 0.000292 AC XY: 212 AN XY: 726948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.000548

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74388

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:26

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:10

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 23, 2021	The BRCA1 c.3296C>T variant is classified as Benign (BS1, BP6) -
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 = 0.0000000000309 -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 25, 2016	- -
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. -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -

not specified Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2014	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 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: Multiple papers descrive as non-pathogenic; ClinVar: 4 B/LB -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided Benign:4

Likely benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA1 p.Pro1099Leu variant was identified in 22 of 114568 proband chromosomes (frequency: 0.0002) from individuals or families with breast or ovarian cancer (Judkins 2005, Simard 2007, Borg 2010). The variant was also identified in the following databases: dbSNP (ID: rs80357201) as "With other allele ", ClinVar (classified as benign by Invitae, Ambry Genetics, GeneDx and 7 other submitters; as likely benign by three submitters; as uncertain significance by one submitter), MutDB, LOVD 3.0 (10x), UMD-LSDB (19x as neutral), BIC Database (23x with no clinical importance), and in ARUP Laboratories (not pathogenic or of no clinical significance). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.4277delC, p.Thr1426Asns*22 and c.5353delA, p.Thr1785Leufs*6), increasing the likelihood that the p.Pro1099Leu variant does not have clinical significance. The variant was not identified in COGR, Cosmic, or Zhejiang University databases. The variant was identified in control databases in 87 of 276300 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 6452 chromosomes (freq: 0.0005), Latino in 17 of 34400 chromosomes (freq: 0.0005), European in 30 of 126188 chromosomes (freq: 0.0002), East Asian in 1 of 18866 chromosomes (freq: 0.00005), Finnish in 14 of 25458 chromosomes (freq: 0.0006), and South Asian in 22 of 30778 chromosomes (freq: 0.0007); it was not observed in the African or Ashkenazi Jewish populations. The p.Pro1099 residue is not 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. A few cancer research articles identified this variant in trans with known deleterious mutations (917delTT and E1060X) in clinical specimens, increasing the likelihood that the p.Pro1099Leu variant does not have clinical significance (Judkins 2005, Judkins 2005, Spurdle 2008). In addition, the variant was classified as neutral with probability of being deleterious is 3.09√ó10-11 by a computational model for BRCA1 and BRCA2 variants that factored in data on segregation, co-occurrence, personal and family histories, and pathology (Lindor 2012). 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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2016	Variant summary: The variant c.3296C>T affects a conserved nucleotide, leading to amino acid change from Pro to Leu. 3/4 in-silico tools predict this variant to be damaging, however they are not definite. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0.00026 (32/122380 chromosomes), which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.001). However, the frequency data should still suggest that this variant is likely to be a rare polymorphism. In reputable databases (BIC and UMD), the variant has been reported to co-occur with multiple deleterious pathogenic variants in BRCA1 (p.Glu1060Ter, c.2376_2376delG and c.798_799delTT) as well as in BRCA2 (c.4277delC and c.5353delA). In addition, the variant is also known to be present with a deleterious BRCA1 variant p.Glu1060Ter (Judkins_2005), a definite evidence for benign outcome. Multifactorial probability model studies also show the variant to have a very low probability of being deleterious. Multiple clinical laboratories, reputable databases, and literature classify this variant as benign/polymorphism. Taken all together, this variant has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 21, 2023	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 31, 2021	- -
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	Vantari Genetics	Jan 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 19, 2015	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 13, 2020

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 21, 2021

- -

BRCA1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;.;.
Eigen	Benign	-0.019
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Uncertain	2.1	M;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-6.7	D;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Uncertain	0.040	D;D;D;D
Polyphen		0.99	D;.;.;P
Vest4		0.38
MVP		0.86
MPC		0.27
ClinPred		0.067	T
GERP RS		3.1
Varity_R		0.14
gMVP		0.14

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: rs80357201; hg19: chr17-41244252;