17-43094585-T-C

Position:

chr17-43094585-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP6_Very_Strong

The NM_007294.4(BRCA1):c.946A>G(p.Ser316Gly) 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 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:4B:11

Conservation

PhyloP100: 0.738

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 -6 ACMG points.

PM1

In a region_of_interest Disordered (size 32) in uniprot entity BRCA1_HUMAN there are 17 pathogenic changes around while only 6 benign (74%) in NM_007294.4

BP6

Variant 17-43094585-T-C is Benign according to our data. Variant chr17-43094585-T-C is described in ClinVar as [Benign]. Clinvar id is 37709.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094585-T-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4 linkuse as main transcript	c.946A>G	p.Ser316Gly	missense_variant	10/23	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.946A>G	p.Ser316Gly	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3		P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000103

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251410

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727236

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:

0.0000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.000103

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000106

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:4Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1

Uncertain:3Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 18, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 22, 2017	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	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 = 2.21E-06 -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 02, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 05, 2018	This alteration is classified as likely 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 07, 2021	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2021	This variant is associated with the following publications: (PMID: 23893897, 16518693, 12531920, 16267036, 15385441, 18273839, 26689913, 26246475, 18284688, 22144684, 25925381, 28477318, 26913838, 27062684, 25479140, 24094589, 33087888) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 13, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 28, 2021	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Sep 17, 2018

Variant summary: BRCA1 c.946A>G (p.Ser316Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 277152 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.7e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.946A>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Lee_2008, Azzollini_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported in the UMD database (BRCA1 c.3228_3229delAG, p.Gly1077ALafsX8; BRCA2 c.6209_6212delAAAG, p.Glu2070ValfsX10), providing supporting evidence for a benign role. Multiple functional studies showed no impact on splicing, no sensitivity increase to ionizing radiation and an HDR assay showed no significant changes from wild-type (Anczukow_2008, Cochran_2015, Lu_2015). 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 x3, likely benign x2, benign x1). Based on the evidence outlined above, the variant was classified as likely benign. -

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

May 23, 2023

- -

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.Ser316Gly variant was identified at least once in a large cohort of 55630 individuals referred for BRCA1 mutation testing (Judkins 2005). The variant was also identified in dbSNP (ID: rs55874646) â€šÃ„ÃºWith non-pathogenic alleleâ€šÃ„Ã¹, LOVD, the BIC database (6X with unknown clinical importance), and in UMD (5X as a unclassified variant). In UMD the variant was listed twice as co-occurring with a pathogenic mutation in either BRCA1 or BRCA2 (BRCA1 c.3228 3229delAG (p.Gly1077AlafsX8) and BRCA2 c.6209 6212delAAAG (p.Glu2070ValfsX10)), increasing the likelihood that this variant does not have clinical significance. In addition, one in silico study suggests that the variant does not confer a high oncogenic risk (Burk-Herrick 2005). The variant was listed in the NHLBI Exome Sequencing Project with a frequency of 0.0002 in European American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Ser316 residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and 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 predicted benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

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

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.83

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

M_CAP

Pathogenic

0.61

MetaRNN

Uncertain

0.62

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H;.;.;.;.;.;.;.

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.7

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

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0060

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.55

MVP

0.98

MPC

0.40

ClinPred

0.59

GERP RS

3.6

Varity_R

0.27

gMVP

0.18

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