rs80357048

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_007294.4(BRCA1):c.4910C>T(p.Pro1637Leu) 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 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:13O:1

Conservation

PhyloP100: 0.768

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP6

Variant 17-43071004-G-A is Benign according to our data. Variant chr17-43071004-G-A is described in ClinVar as [Benign]. Clinvar id is 55314.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43071004-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4 link	c.4910C>T	p.Pro1637Leu	missense_variant	Exon 15 of 23	ENST00000357654.9	NP_009225.1	P38398-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9 link	c.4910C>T	p.Pro1637Leu	missense_variant	Exon 15 of 23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251356

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135868

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:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727244

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:

0.0000504

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:13Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:1Benign:4Other:1

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 10, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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 = 0.0000627 -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:4

Apr 07, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 01, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 09, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS3_, BP1_Strong, BP5_VeryStrong, c.4910C>T, located in exon 15 (16 according to BIC nomenclature) of the BRCA1 gene, is predicted to result in the substitution of proline by leucine at codon 1637, p.(Pro1637Leu). This position is outside a (potentially) clinically important functional domain and, moreover, the SpliceAI algorithm predicts no significant impact on splicing (BP1_strong). This variant is found in 5/268222 alleles at a frequency of 0.001% in the gnomAD v2.1.1 database, non-cancer dataset. Two calibrated studies have reported this variant to affect protein function similar to benign control variants (PMIDs:30209399, 30765603) (BS3). The combined LR against pathogenicity, based on multifactorial likelihood clinical data, is <0.0028 (BP5_VeryStrong). This variant has been reported in the ClinVar database (6x benign, 5x likely benign, 2x uncertain significance), and in the LOVD (2x likely benign, 2x uncertain significance) and the BRCA Exchange database (classified as benign). Based on currently available information, the variant c.4910C>T should be considered a benign variant, according to ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.0.0. -

not provided

Benign:2

Mar 22, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant Summary: This variant involves alteration of a non-conserved nucleotide and 2/4 in silico tools predict a benign outcome (SNP&GO not captured here due to low reliability index). This variant was found in 3/121924 control chromosomes at a frequency of 0.0000246, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0010005). Variant has been reported in multiple affected individuals without evidence for causality. In particular, this variant is found to commonly co-occur with the BRCA1 pathogenic variant c.2457delC (internal data, BIC database, Humphrey_1997, and Tavtigian_2006), suggesting this variant of interest is in linkage disequilibrium and has been suggested to be a rare polymorphism per Humphrey_1997. In addition, multiple publications (Easton_2007, Lindor_2012 and Humphrey_1997), clinical labs, and databases (ARUP, ClinVar, Invitae, SCRP) classify the variant as benign/likely benign. Functional studies suggest that the variant acts comparably to wild-type (Humphrey_1997 and Coyne_2004). Considering all, variant is classified as Benign. -

Sep 21, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25782689, 22753008, 15004537, 18284688, 16014699, 17924331, 7939630, 9159158, 26689913, 21990134, 24448499, 11183185, 28398198, 28781887, 30209399, 30765603, 33087888) -

not specified

Uncertain:1

Aug 11, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: Classified as benign by expert panel (8/10/15) -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.Pro1637Leu variant was identified in 1 of 858 proband chromosomes (frequency: 0.001) from individuals or families with ovarian cancer (Kanchi 2014). The variant was also identified in dbSNP (ID: rs80357048) as "With Uncertain significance, other alleleâ€šÃ„Ã¹, ClinVar (classified as benign by Invitae, Ambry Genetics and four other submitters; as likely benign by two submitters and as uncertain significance by two submitters), MutDB , LOVD 3.0 (8x), UMD-LSDB (6x as unclassified variant), BIC Database (67x with unknown significance), and in ARUP Laboratories (not pathogenic or of no clinical significance). The variant was not identified in the COGR, Cosmic, or Zhejiang University, databases. The variant was identified in control databases in 5 of 246118 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 5 of 111576 chromosomes (freq: 0.00005), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Pro1637 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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. The multifactorial probability based model determined the variant has posterior probability of being deleterious 6.27âˆšÃ³10-5 and predicted to be neutral with odds of neutrality = 493 (Lindor 2012, Easton 2007). In addition, in several publications the variant observed with one or more known truncating mutations (Kanchi 2014, Tavtigian 2006), increasing the likelihood that the p.Pro1637Leu variant does not have clinical significance. 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. -

BRCA1-related disorder

Benign:1

Feb 18, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

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

Eigen

Benign

0.068

Eigen_PC

Benign

-0.071

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.82

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

M_CAP

Pathogenic

0.46

MetaRNN

Uncertain

0.53

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

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.9

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

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-4.4

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

REVEL

Uncertain

0.57

Sift

Uncertain

0.012

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

Sift4G

Uncertain

0.0040

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

Polyphen

0.36, 0.99

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

Vest4

0.31

MVP

0.91

MPC

0.087

ClinPred

0.23

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.039

gMVP

0.27

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