rs201596327

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007294.4(BRCA1):c.626C>T(p.Pro209Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,812 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 1.53

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17694008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.626C>T	p.Pro209Leu	missense_variant	9/23	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.626C>T	p.Pro209Leu	missense_variant	9/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152140

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:

0.000577

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:

0.00000398

AC:

AN:

250978

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

0.00000889

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000328

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:

152258

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74442

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

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 16, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 19, 2023	The p.P209L variant (also known as c.626C>T), located in coding exon 8 of the BRCA1 gene, results from a C to T substitution at nucleotide position 626. The proline at codon 209 is replaced by leucine, an amino acid with similar properties. In one study, this alteration was reported with a carrier frequency of 11 in 7051 unselected breast cancer patients and 20 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant has also been reported in additional Japanese and Korean patients with personal and/or family histories of breast and/or ovarian cancer (Sugano K et al. Cancer Sci. 2008 Oct;99:1967-76; Nakamura S et al. Breast Cancer. 2015 Sep;22:462-8; Park KS et al. Genet. Med. 2016 Dec;18:1250-1257; Ahmadloo S et al. J. Hum. Genet. 2017 Apr;62:561-567; Ryu JM et al. Breast. 2017 Jun;33:109-116; Arai M et al. J. Hum. Genet., 2018 Apr;63:447-457). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 06, 2024

Variant summary: BRCA1 c.626C>T (p.Pro209Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 276206 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (8e-05 vs 0.001), allowing no conclusion about variant significance. However, this variant has been reported at a frequency of 0.0013 in Japanese population (Ahmadloo_2017). c.626C>T has been reported in the literature in individuals affected with breast and/or ovarian cancer, and multiple primary cancer (Ahmadloo_2017, Nakamura_2013, Park_2016, Ryu_2017, Sugano_2008, Fujitani_2023). One large case-control study evaluating Biliary tract cancer genetic risk also reported this variant was not significantly enriched in the case cohorts (Okawa_2023).These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28179634, 29176636, 33309985, 30287823, 24249303, 36243179, 27124784, 28364669, 19016756). ClinVar contains an entry for this variant (Variation ID: 409315). Based on the evidence outlined above, the variant was classified as uncertain significance. -

BRCA1-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 29, 2024

This missense variant replaces proline with leucine at codon 209 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals with personal or family history of breast and/or ovarian cancer in East Asia (PMID: 19016756, 24249303, 27124784, 28179634, 29176636). However, one study reported a co-occurring pathogenic missense variant in BRCA1, p.Leu1780Pro (PMID: 28364669) and a multifactorial analysis reported a posterior probability of being deleterious of 0.00221 (PMID: 27124784). Case-control studies in the Japanese population has reported this variant in 11/7051 female breast cancer cases and 20/11241 unaffected females (OR = 0.88 and 95% CI 0.4 to 1.9) and in 1/1005 pancreatic cancer cases and 35/23705 unaffected individuals (OR = 0.7 (95% CI 0 to 4) (PMID: 30287823, 32980694). This variant has been identified in 1/250978 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant is not associated with BRCA1-associated disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Dec 20, 2019

- -

BRCA1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2023

The BRCA1 c.626C>T variant is predicted to result in the amino acid substitution p.Pro209Leu. This variant has been reported in individuals with breast and/or ovarian cancer (Ahmadloo et al. 2017. PubMed ID: 28179634; Ryu et al. 2017. PubMed ID: 28364669; Arai et al. 2018. PubMed ID: 29176636; Supplementary Data File S1, Kim et al. 2020. PubMed ID: 31907386). Of note this variant has also been reported in control populations (Momozawa et al. 2018. PubMed ID: 30287823) and is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41247907-G-A). This variant is also reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/409315/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 209 of the BRCA1 protein (p.Pro209Leu). This variant is present in population databases (rs201596327, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer as well as healthy individuals (PMID: 19016756, 27124784, 28179634, 28364669, 30287823). ClinVar contains an entry for this variant (Variation ID: 409315). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

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

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.89

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

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.18

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

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

1.4

L;L;L;L;.;L;.;.;.;.;.;.;.

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.0

D;N;N;N;N;N;D;N;N;N;N;N;D

REVEL

Uncertain

0.54

Sift

Benign

0.27

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

Sift4G

Benign

0.70

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

Polyphen

0.015, 1.0, 0.020

.;B;.;.;.;D;.;.;B;.;.;.;.

Vest4

0.30

MutPred

0.32

Loss of disorder (P = 0.0461);Loss of disorder (P = 0.0461);Loss of disorder (P = 0.0461);Loss of disorder (P = 0.0461);.;Loss of disorder (P = 0.0461);.;.;Loss of disorder (P = 0.0461);Loss of disorder (P = 0.0461);.;Loss of disorder (P = 0.0461);.;

MVP

0.72

MPC

0.083

ClinPred

0.079

GERP RS

3.6

Varity_R

0.027

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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